Formulations for oral administration of active agents

ABSTRACT

A pharmaceutical composition for oral administration is disclosed herein, comprising a therapeutically active agent, SNAC and at least one antacid compound. Further disclosed herein is a pharmaceutical composition unit dosage form for oral administration of a therapeutically active agent is provided herein, the unit dosage form comprising: a core comprising the therapeutically active agent and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate); and an external layer comprising at least one protective agent selected from the group consisting of an antacid compound and a protease inhibitor. Methods and uses utilizing the aforementioned pharmaceutical compositions, as well as methods and uses utilizing co-administration, by oral administration, of at least one antacid composition, and a composition comprising the therapeutically active agent and SNAC, are further disclosed herein, for use in treating a condition treatable by oral administration of the therapeutically active agent.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/549,436 filed on Aug. 8, 2017, which is a National Phase of PCTPatent Application No. PCT/IL2016/050155 having International FilingDate of Feb. 9, 2016, which claims the benefit of priority under 35 USC§ 119(e) of U.S. Provisional Patent Application Nos. 62/113,600,62/113,629, 62/113,604, 62/113,673, 62/113,638, 62/113,625 and62/113,619, all filed on Feb. 9, 2015. The contents of the aboveapplications are all incorporated by reference as if fully set forthherein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to drugdelivery, and more particularly, but not exclusively, to formulationsand/or systems for oral administration of therapeutically active agentssuch as, for example, therapeutically active polypeptides (e.g.,proteins).

Oral administration of peptide pharmaceuticals is problematic due todegradation of peptides and/or proteins in the digestive system and poorabsorption of large molecules.

U.S. Patent Application Publication No. 2007/0087957 describescompositions for oral administration of a protein, the compositionscomprising a protein and an omega-3 fatty acid, as well as the use ofsuch compositions for oral administration of insulin.

Qi & Ping [J Microencapsulation 2004, 21:37-45] describe administrationof enteric microspheres containing insulin with SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric microspheres are forprotecting the insulin from digestive enzymes of the stomach and smallintestine, and the SNAC is for enhancing absorption.

U.S. Patent Application Publication No. 2011/0142800 describescompositions for oral administration of a protein, comprising a proteinhaving a molecular weight of up to 100,000 Da, a protease inhibitor, andan absorption enhancer, such as SNAC,N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC),8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB) and sodiumsalts thereof.

International Patent Application Publication WO 00/48589 describes solidoral dosage forms comprising a heparin drug in admixture with SNAC orSNAD for facilitating absorption and/or enhancing bioavailability of theheparin drug, wherein the heparin drug is reported to protect the SNACor SNAD from precipitation during transit through acidic regions of thegastrointestinal tract.

U.S. Pat. No. 8,110,547 describes compositions for buccal administrationof parathyroid hormone (PTH). The composition comprises PTH or afragment or analog thereof, as well as a delivery agent such as 4-MOAC,SNAC, SNAD, 5-CNAC and 4-CNAB.

Parathyroid hormone (PTH) is secreted by the parathyroid gland as apolypeptide containing 84 amino acids. PTH has been reported to enhancebone growth when administered intermittently, with circulating levelsreturning to control levels within 3 hours [Martin, J Bone Metab 2014,21:8-20]. In contrast, prolonged elevated PTH levels enhance release ofcalcium from bones (bone resorption).

Additional background art includes Qi et al. [Acta Pharm Sinica 2004,39:844-848]; International Patent Application Publications WO 00/50386,WO 01/32130, WO 01/32596, WO 03/045306 and WO 2007/121471; JapanesePatent Application Nos. 2005281231 and 2006111558; and U.S. PatentApplication Publication Nos. 2006/0234913 and 2013/0224300.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition unit dosage form for oraladministration of a therapeutically active agent, the unit dosage formcomprising:

-   -   a core comprising the therapeutically active agent and SNAC        (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate); and    -   an external layer comprising at least one protective agent        selected from the group consisting of an antacid compound and a        protease inhibitor.

According to an aspect of some embodiments of the invention, there isprovided a use of a unit dosage form described herein in the preparationof a medicament for use in the treatment of a condition treatable byoral administration of the therapeutically active agent in a subject inneed thereof.

According to an aspect of some embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof, the method comprising orally administering to the subject aunit dosage form described herein to a subject in need thereof.

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition for oral administration of atherapeutic active agent, the composition comprising a therapeuticallyactive agent, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), and atleast one antacid compound.

According to an aspect of some embodiments of the invention, there isprovided a use of a composition described herein in the preparation of amedicament for use in the treatment of a condition treatable by oraladministration of the therapeutically active agent in a subject in needthereof.

According to an aspect of some embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof, the method comprising orally administering to the subject acomposition described herein to a subject in need thereof.

According to an aspect of some embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof, the method comprising co-administering to the subject, by oraladministration, an antacid composition comprising at least one antacidcompound and/or at least one gastric acid secretion inhibitor, and acomposition comprising the therapeutically active agent and SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate).

According to an aspect of some embodiments of the invention, there isprovided a composition comprising a therapeutically active agent andSNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), for use in thetreatment of a condition treatable by oral administration of thetherapeutically active agent in a subject in need thereof, wherein thetreatment comprises co-administering an antacid composition comprisingat least one antacid compound and/or at least one gastric acid secretioninhibitor.

According to an aspect of some embodiments of the invention, there isprovided a use of a composition comprising a therapeutically activeagent and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) in thepreparation of a medicament for use in the treatment of a conditiontreatable by oral administration of the therapeutically active agent ina subject in need thereof, wherein the treatment comprisesco-administering an antacid composition comprising at least one antacidcompound and/or at least one gastric acid secretion inhibitor.

According to some embodiments of the invention, the external layer isdevoid of the therapeutically active agent.

According to some embodiments of the invention, the external layer isdevoid of SNAC.

According to some embodiments of the invention, the external layercomprises at least one protease inhibitor.

According to some embodiments of the invention, the unit dosage form iscoated with an enteric coating.

According to some embodiments of the invention, the external layercomprises at least one antacid compound.

According to some embodiments of the invention, the core comprises atleast one antacid compound.

According to some embodiments of the invention, the unit dosage form isin a form of a tablet comprising the core and the external layer.

According to some embodiments of the invention, at least 90 weightpercents of the tablet consists of ingredients selected from the groupconsisting of the therapeutically active agent, SNAC, and the at leastone protective agent.

According to some embodiments of the invention, the core and/or theexternal layer further comprises a pharmaceutically acceptable carrier.

According to some embodiments of the invention, the unit dosage form isformulated such that absorption of the therapeutically active agentfollowing oral administration of the unit dosage form is characterizedby a bioavailability of the therapeutically active agent which is atleast 10% higher than a bioavailability of the therapeutically activeagent following oral administration of the core without the externallayer.

According to some embodiments of the invention, the composition furthercomprises at least one protease inhibitor.

According to some embodiments of the invention, the at least one antacidcompound is selected from the group consisting of calcium carbonate,calcium gluconate, calcium citrate, sodium carbonate, sodiumbicarbonate, sodium gluconate, sodium citrate, sodium hydroxide,potassium carbonate, potassium bicarbonate, potassium gluconate,potassium citrate, potassium hydroxide, magnesium carbonate, magnesiumgluconate, magnesium citrate, magnesium hydroxide, magnesium oxide,aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminumhydroxide.

According to some embodiments of the invention, at least 90 weightpercents of the composition consists of ingredients selected from thegroup consisting of the therapeutically active agent, SNAC, and the atleast one antacid compound.

According to some embodiments of the invention, the composition isformulated such that absorption of the therapeutically active agentfollowing oral administration of the composition is characterized by abioavailability of the therapeutically active agent which is at least10% higher than a bioavailability of the therapeutically active agentfollowing oral administration of a composition comprising thetherapeutically active agent and the SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate) without the at least one antacidcompound.

According to some embodiments of the invention, the composition is in aform of a homogeneous mixture.

According to some embodiments of the invention, the composition isformulated as a unit dosage form.

According to some embodiments of the invention, the unit dosage formcomprises at least 50 mg of SNAC.

According to some embodiments of the invention, the unit dosage form isa solid unit dosage form.

According to some embodiments of the invention, the composition isformulated as a tablet.

According to some embodiments of the invention, the unit dosage form issoluble in gastric fluid.

According to some embodiments of the invention, the unit dosage formdissolves in gastric fluid in no more than 60 minutes.

According to some embodiments of the invention, the unit dosage form isfor use in the treatment of a condition treatable by oral administrationof the therapeutically active agent in a subject in need thereof.

According to some embodiments of the invention, the composition is foruse in the treatment of a condition treatable by oral administration ofthe therapeutically active agent in a subject in need thereof.

According to some embodiments of the invention, the co-administeringcomprises administering the antacid composition prior to orconcomitantly with the composition comprising the therapeutically activeagent and SNAC.

According to some embodiments of the invention, at least one of theantacid composition and the composition comprising the therapeuticallyactive agent and SNAC further comprises at least one protease inhibitor.

According to some embodiments of the invention, the at least one antacidcompound and/or at least one gastric acid secretion inhibitor isselected from the group consisting of calcium carbonate, calciumgluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodiumgluconate, sodium citrate, sodium hydroxide, potassium carbonate,potassium bicarbonate, potassium gluconate, potassium citrate, potassiumhydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate,magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminumgluconate, aluminum citrate, aluminum hydroxide, cimetidine, famotidine,nizatidine, ranitidine, omeprazole, lansoprazole, dexlansoprazole,esomeprazole, rabeprazole and ilaprazole.

According to some embodiments of the invention, the antacid compositionand the composition comprising the therapeutically active agent and SNACare each soluble in gastric fluid.

According to some embodiments of the invention, each of theaforementioned compositions dissolves in gastric fluid in no more than60 minutes.

According to some embodiments of the invention, absorption of thetherapeutically active agent following the co-administering ischaracterized by a bioavailability of the therapeutically active agentwhich is at least 10% higher than a bioavailability of thetherapeutically active agent following oral administration of thecomposition comprising the therapeutically active agent and the SNAC(sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) without co-administeringthe antacid composition.

According to some embodiments of the invention, the at least oneprotease inhibitor comprises at least one trypsin inhibitor.

According to some embodiments of the invention, the at least one trypsininhibitor is selected from the group consisting of is lima bean trypsininhibitor, aprotinin, soybean trypsin inhibitor and ovomucoid trypsininhibitor.

According to some embodiments of the invention, the at least one trypsininhibitor comprises soybean trypsin inhibitor.

According to some embodiments of the invention, the therapeuticallyactive agent has a molecular weight in a range of 0.5 kDa to 100 kDa.

According to some embodiments of the invention, the therapeuticallyactive agent is a polypeptide.

According to some embodiments of the invention, the polypeptide isselected from the group consisting of a parathyroid hormone, insulin, aglucagon, an interferon, a growth hormone, an erythropoietin, acalcitonin, an omentin, a motilin, a leptin, a peptide YY, a GLP-1, aGLP-2, a granulocyte colony stimulating factor (G-CSF), an antibody, aninterleukin, an erythropoietin, a vasopressin, a vasoactive intestinalpeptide, a pituitary adenylate cyclase-activating peptide (PACAP), ablood clotting factor, an endomorphin, a TNF inhibitor, disitertide,octreotide, davunetide, icatibant, glucocerebrosidase, a gonadotropinreleasing hormone, acyline, and a GLP-1 agonist.

According to some embodiments of the invention, the polypeptide isselected from the group consisting of parathyroid hormone and a fragmentthereof.

According to some embodiments of the invention, the polypeptidecomprises teriparatide.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIGS. 1A-1C depict exemplary unit dosage forms according to someembodiments of the invention;

FIGS. 2A-2C depict exemplary coated unit dosage forms according to someembodiments of the invention;

FIG. 3 depicts an exemplary tablet according to some embodiments of theinvention;

FIG. 4 depicts an exemplary coated tablet according to some embodimentsof the invention;

FIG. 5 depicts an exemplary external layer of a unit dosage formaccording to some embodiments of the invention;

FIG. 6 depicts an exemplary external layer of a unit dosage formaccording to some embodiments of the invention;

FIG. 7 depicts an exemplary core of a unit dosage form according to someembodiments of the invention;

FIG. 8 presents a graph showing the release of SNAC, as a function oftime, from an exemplary tablet formulation comprising sodium bicarbonateand from a control tablet formulation without sodium bicarbonate; and

FIG. 9 presents a bar graph showing relative absorption of teriparatidefrom an exemplary oral formulation co-administered with 150 ml of water(H2O) or with an aqueous solution of 3 mg/ml sodium bicarbonate(H2O+NaCO3) (absorption upon co-administration with water defined as100%).

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to drugdelivery, and more particularly, but not exclusively, to formulationsand/or systems for oral administration of therapeutically active agentssuch as, for example, therapeutically active polypeptides (e.g.,proteins).

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

While investigating the enhancement of absorption of therapeuticallyactive agents by SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) uponoral administration, the present inventors have uncovered that suchcompositions are significantly affected by inactivation of the SNAC, anabsorption enhancer, upon contact with stomach acid, which converts SNACfrom a soluble carboxylate salt to an insoluble carboxylic acid. Theinactivation of SNAC reduces the absorption of the therapeuticallyactive agent, thereby reducing the efficacy of the composition.Furthermore, many therapeutically active agents are at least partiallyinactivated upon contact with stomach acid, which further reduces theefficacy of such compositions. In addition, protease inhibitors used toprotect therapeutically active agents from proteolysis may also be atleast partially inactivated upon contact with stomach acid, which mayfurther reduce the efficacy of such compositions.

The inventors have further uncovered that the ability of proteaseinhibitors to protect therapeutically active agents against proteaseactivity in the digestive system is limited, because much of thetherapeutically active agent is inactivated by proteases before theproteases are inhibited by the protease inhibitor.

In order to overcome the abovementioned problems, the present inventorshave designed compositions and unit dosage forms utilizing an agent forprotecting the SNAC and/or the therapeutically active agent from stomachacid, thereby allowing increased absorption of the therapeuticallyactive agent (e.g., via protection of the therapeutically active agent)and/or by absorption over a longer period of time (e.g., by protectionof SNAC). Such a protective agent may be, for example, an antacid and/oran enteric coating.

The present inventors have further designed unit dosage forms so as torelease a protective agent prior to release of the compound which theprotective agent is intended to protect, for example, releasing anantacid for reducing acidity in a vicinity of an orally administeredcomposition prior to exposure of SNAC and/or a therapeutically activeagent to stomach acid, and/or releasing a protease inhibitor forinhibiting proteases prior to exposure of a therapeutically active agentto proteases.

According to one aspect of embodiments of the invention, there isprovided a pharmaceutical composition unit dosage form for oraladministration of a therapeutically active agent, the unit dosage formcomprising a core and an external layer. The core comprises thetherapeutically active agent and SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate); and the external layer comprisesat least one protective agent.

Herein, the term “protective agent” refers to an agent capable ofprotecting the therapeutically active agent and/or SNAC against enzymesand/or acid in the gastrointestinal tract. For example, a proteaseinhibitor can protect a therapeutically active agent from activity of aprotease, and an antacid can protect SNAC (e.g., by reducing conversionof SNAC from a carboxylate salt to a carboxylic acid form) and/or atherapeutically active agent from stomach acid.

In some of any of the embodiments described herein, the protective agentis a protease inhibitor.

Herein throughout, the term “protease inhibitor” refers to a compoundwhich reduces a proteolytic activity of a protease, for example, aproteolytic activity which inactivates a therapeutically active agentdescribed herein. The term “protease inhibitor” encompasses, forexample, both large molecules (e.g., proteins) and small molecules, aswell as both naturally occurring compounds and synthetic compounds.

In some of any of the embodiments described herein, the protective agentis an antacid compound.

In some of any of the embodiments described herein, the unit dosage formcomprises at least one protective agent which is an antacid compound andat least one protective agent which is a protease inhibitor.

Herein throughout, the term “antacid compound” refers to anypharmaceutically acceptable compound capable of neutralizing stomachacid (e.g., HCl in aqueous solution), preferably wherein one mole ofantacid compound is capable of neutralizing at least 0.5 mole of HCl,and more preferably capable of neutralizing at least 1 mole of HCl. Thetherapeutically active agent, SNAC and protease inhibitors describedherein are excluded from the scope of the phrase “antacid compound”,even though they may exhibit some ability to neutralize stomach acid, insome embodiments of the invention.

Examples of antacid compounds which may be used in any one of theembodiments described herein relating to one or more antacid compounds(in accordance with any of the aspects of embodiments of the inventiondescribed herein), include, without limitation, calcium carbonate,calcium gluconate, calcium citrate, sodium carbonate, sodiumbicarbonate, sodium gluconate, sodium citrate, sodium hydroxide,potassium carbonate, potassium bicarbonate, potassium gluconate,potassium citrate, potassium hydroxide, magnesium carbonate, magnesiumgluconate, magnesium citrate, magnesium hydroxide, magnesium oxide,aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminumhydroxide.

The unit dosage form may have any shape suitable for orally administeredpharmaceutical dosage forms, including, without limitation, any3-dimensional shape having a substantially rectangular (includingsubstantially square), substantially circular and/or substantially ovalcross-section along at least one axis. For example, the unit dosage formmay have a substantially box-like shape, having a substantiallyrectangular cross-section (optionally with rounded corners) along 3axes; a substantially cylindrical shape, having substantially circularand/or substantially oval cross-section along one axis, and asubstantially rectangular cross-section (optionally with roundedcorners) along 2 axes; or a substantially spherical or ovoid shape,having a substantially circular and/or substantially oval cross-sectionalong 3 axes.

In some of any one of the embodiments described herein, the externallayer comprises one or more protease inhibitors and one or more antacidcompounds. In some such embodiments, the external layer consistsessentially of one or more protease inhibitors and one or more antacidcompounds. Alternatively, in some such embodiments, the external layercomprises a combination of one or more excipients with the proteaseinhibitor(s) and antacid compound(s).

In some of any one of the embodiments described herein, the externallayer comprises one or more protease inhibitors, and is devoid ofantacid compounds. In some such embodiments, the external layer consistsessentially of one or more protease inhibitors. Alternatively, in somesuch embodiments, the external layer comprises a combination of one ormore excipients with the protease inhibitor(s).

In some of any one of the embodiments described herein, the externallayer comprises one or more antacid compounds, and is devoid of proteaseinhibitors. In some such embodiments, the external layer consistsessentially of one or more antacid compounds. Alternatively, in somesuch embodiments, the external layer comprises a combination of one ormore excipients with the antacid compound(s).

Herein throughout, the phrase “devoid of” encompasses the presence ofminute amounts of the indicated substance (for example, less than 0.1weight percent, optionally less than 0.05 weight percent, optionallyless than 0.02 weight percent, and optionally less than 0.01 weightpercent) as well as the complete absence of the indicated substance.

In some of any one of the embodiments described herein, a concentration(as a weight percentage) of therapeutically active agent in the externallayer is lower than a concentration of the therapeutically active agentin the core. In some of any one of the embodiments described herein, aconcentration (as a weight percentage) of therapeutically active agentin the external layer is less than 50% of a concentration of thetherapeutically agent in the core. In some embodiments, theconcentration in the external layer is less than 20% of theconcentration in the core. In some embodiments, the concentration in theexternal layer is less than 10% of the concentration in the core. Insome embodiments, the concentration in the external layer is less than5% of the concentration in the core. In some embodiments, theconcentration in the external layer is less than 2% of the concentrationin the core. In some embodiments, the concentration in the externallayer is less than 1% of the concentration in the core. In someembodiments, the external layer is devoid of the therapeutically activeagent.

In some of any one of the embodiments described herein, a concentration(as a weight percentage) of SNAC in the external layer is lower than aconcentration of SNAC in the core. In some of any one of the embodimentsdescribed herein, a concentration (as a weight percentage) of SNAC inthe external layer is less than 50% of a concentration of SNAC in thecore. In some embodiments, the concentration in the external layer isless than 20% of the concentration in the core. In some embodiments, theconcentration in the external layer is less than 10% of theconcentration in the core. In some embodiments, the concentration in theexternal layer is less than 5% of the concentration in the core. In someembodiments, the concentration in the external layer is less than 2% ofthe concentration in the core. In some embodiments, the concentration inthe external layer is less than 1% of the concentration in the core. Insome embodiments, the external layer is devoid of SNAC. In someembodiments, the external layer is devoid of the therapeutically activeagent and devoid of SNAC.

In some of any one of the embodiments described herein, the externallayer covers the whole surface of the core.

In some of any one of the embodiments described herein, the externallayer does not cover the whole surface of the core. In some embodimentswherein the external layer does not cover the whole surface of the core,the external layer is separated into a plurality of unconnected layers(e.g., 2 layers, 3 layers, 4 layers, or more than 4 layers), each of theunconnected layers covering a different region of the surface of thecore. In such embodiments, the phrase “external layer” referscollectively to all such unconnected layers. In some embodiments, theexternal layer is separated into two unconnected layers which coveropposite sides of the core. In alternative embodiments wherein theexternal layer does not cover the whole surface of the core, theexternal layer is in a form of a single continuous layer.

In some of any one of the embodiments described herein, the externallayer covers at least 30% of the surface area of the core. In someembodiments, the external layer covers at least 40% of the surface areaof the core. In some embodiments, the external layer covers at least 50%of the surface area of the core. In some embodiments, the external layercovers at least 60% of the surface area of the core. In someembodiments, the external layer covers at least 70% of the surface areaof the core. In some embodiments, the external layer covers at least 80%of the surface area of the core. In some embodiments, the external layercovers at least 90% of the surface area of the core.

In some embodiments of any one of the embodiments described herein, theprotease inhibitor(s) and/or antacid compound(s) in the external layerare distributed homogeneously throughout the external layer.

In some embodiments of any one of the embodiments described herein, theprotease inhibitor(s) and/or antacid compound(s) in the external layerare distributed inhomogeneously throughout the external layer.

In some such embodiments, the protease inhibitor(s) and/or antacidcompound(s) are within particles (e.g., microspheres containing theprotease inhibitor(s) and/or antacid compound(s)), and the externallayer further comprises a material (e.g., a filler and/or binder)between the particles.

Alternatively or additionally, in some embodiments, the external layercomprises two or more layers (e.g., concentric layers), wherein eachlayer within the external layer has a different composition. Forexample, the external layer may optionally comprise a first layer whichcomprises one of the protease inhibitor(s) and/or antacid compound(s), asecond layer which comprises another of the protease inhibitor(s) and/orantacid compound(s), and optionally one or more additional layers, eachcomprising different inhibitor(s) and/or antacid compound(s).

In some embodiments of any one of the embodiments described herein, thecore further comprises one or more protease inhibitors and/or antacidcompounds, in addition to a therapeutically active agent and SNAC.

In some embodiments of any one of the embodiments described herein, thecore consists essentially of the therapeutically active agent and SNACor a combination of the therapeutically active agent, SNAC and theprotease inhibitor(s) and/or antacid compound(s).

In some embodiments of any one of the embodiments described herein, thecore comprises a combination of one or more excipients with thetherapeutically active agent and SNAC (and optionally the proteaseinhibitor(s) and/or antacid compound(s)).

In some embodiments of any one of the embodiments described herein, thecore comprises a therapeutically active agent, SNAC and one or moreantacid compounds. In some embodiments, the core consists essentially ofa combination of the therapeutically active agent, SNAC and the antacidcompound(s). Alternatively, in some embodiments, the core comprises acombination of one or more excipients with the therapeutically activeagent, SNAC and antacid compound(s).

In some embodiments of any one of the embodiments described herein, thecore comprises a therapeutically active agent, SNAC and one or moreprotease inhibitors. In some embodiments, the core consists essentiallyof a combination of the therapeutically active agent, SNAC and theprotease inhibitor(s). Alternatively, in some embodiments, the corecomprises a combination of one or more excipients with thetherapeutically active agent, SNAC and protease inhibitor(s).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent and/or SNAC in the core are distributedhomogeneously throughout the core.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent and/or SNAC in the core are distributedinhomogeneously throughout the core.

In some such embodiments, the therapeutically active agent and/or SNACare within particles (e.g., microspheres containing the therapeuticallyactive agent and/or SNAC), and the core comprises a material (e.g., afiller and/or binder) between the particles.

Alternatively or additionally, in some embodiments, the core comprisesan inner portion and an outer portion (e.g., configured concentrically),wherein each portion within the core has a different composition. Forexample, the core may optionally comprise an outer portion whichcomprises the therapeutically active agent and an inner portion whichcomprises SNAC, or vice versa.

In some of any one of the embodiments described herein, the unit dosageform further comprises a coating which coats the outer surface of theexternal layer described herein, and optionally also a region of a coresurface which is not covered by an external layer (in embodimentswherein the external layer does not cover the whole core). In someembodiments, the coating is formed from material which dissolves in atleast a portion of the gastrointestinal tract.

In some embodiments of any one of the embodiments described herein, thecoating is an enteric coating, that is, a coating which dissolves underconditions in the intestines (e.g., in an aqueous environment having apH of at least 5.5 and/or in the presence of colonic bacteria), therebyexposing the external layer, but does not dissolve under conditions inthe stomach (e.g., in an aqueous environment having a pH in a range offrom 1 to 3.5). An enteric coating may optionally dissolve in theduodenum, optionally in the jejunum, optionally in the ileum, andoptionally in the colon. Many enteric coatings are known in the art, andthe skilled person will be readily capable of selecting and preparing asuitable enteric coating for dissolving in a pre-determined region ofthe intestines.

In some embodiments of any one of the embodiments described herein, thecoating dissolves under conditions in the stomach (e.g., in an aqueousenvironment, optionally only when a low pH is present), thereby exposingthe external layer. Such a coating is optionally adapted for altering anappearance of the unit dosage form (e.g., for aesthetic enhancementand/or labeling), to provide flavor and/or mask flavor, and/or toprotect the external layer and/or core (e.g., from mechanical insult,air, light and/or liquids).

Dissolution of the unit dosage form in the gastrointestinal systeminitially comprises primarily dissolution of the external layer(optionally after dissolution of a coating, if present), therebyreleasing the protease inhibitor(s) and/or antacid compound(s) in theexternal layer prior to release of therapeutically active agent and SNACfrom the core.

In some embodiments of any one of the embodiments described herein, theunit dosage form is formulated as a tablet. In some embodiments, theunit dosage form is formulated as a multi-layered tablet (e.g., a3-layered tablet), in which the external layer forms an upper layer anda lower layer, and the core is formulated as a middle layer sandwichedbetween the upper layer and a lower layer. Exemplary tablets are shownin FIGS. 3 and 4 herein. Any of the multi-layered tablets describedherein may optionally prepared according to any technique known in theart for preparing multi-layered tablets (e.g., 3-layered tablet),including, without limitation a technique described by Shende et al.[Int J Drug Delivery 2012, 4:418-426], the contents of which areincorporated herein by reference.

In some embodiments of any one of the embodiments described herein, theunit dosage form consists primarily of the combination oftherapeutically active agent, SNAC, and at least one protective agent(protease inhibitor(s) and/or antacid compound(s)) described herein,that is, at least 50 weight percents of the unit dosage form consists ofingredients selected from the group consisting of a therapeuticallyactive agent, SNAC and at least one protective agent. In someembodiments, at least 60 weight percents of the unit dosage formconsists of a therapeutically active agent, SNAC and at least oneprotective agent. In some embodiments, at least 70 weight percents ofthe unit dosage form consists of a therapeutically active agent, SNACand at least one protective agent. In some embodiments, at least 80weight percents of the unit dosage form consists of a therapeuticallyactive agent, SNAC and at least one protective agent. In someembodiments, at least 90 weight percents of the unit dosage formconsists of a therapeutically active agent, SNAC and at least oneprotective agent. In some embodiments, at least 95 weight percents ofthe unit dosage form consists of a therapeutically active agent, SNACand at least one protective agent. In some embodiments, at least 98weight percents of the unit dosage form consists of a therapeuticallyactive agent, SNAC and at least one protective agent. In someembodiments, the unit dosage form is formulated as a tablet.

In some embodiments of any one of the embodiments described herein, theexternal layer and core described herein consist primarily of thecombination of therapeutically active agent, SNAC, and at least oneprotective agent (protease inhibitor(s) and/or antacid compound(s))described herein, that is, at least 50 weight percents of the totalweight of the external layer and core consists of ingredients selectedfrom the group consisting of a therapeutically active agent, SNAC and atleast one protective agent. In some embodiments, at least 60 weightpercents of the total weight of the external layer and core consists ofa therapeutically active agent, SNAC and at least one protective agent.In some embodiments, at least 70 weight percents of the total weight ofthe external layer and core consists of a therapeutically active agent,SNAC and at least one protective agent. In some embodiments, at least 80weight percents of the total weight of the external layer and coreconsists of a therapeutically active agent, SNAC and at least oneprotective agent. In some embodiments, at least 90 weight percents ofthe total weight of the external layer and core consists of atherapeutically active agent, SNAC and at least one protective agent. Insome embodiments, at least 95 weight percents of the total weight of theexternal layer and core consists of a therapeutically active agent, SNACand at least one protective agent. In some embodiments, at least 98weight percents of the total weight of the external layer and coreconsists of a therapeutically active agent, SNAC and at least oneprotective agent. In some embodiments, the external layer and core areformulated as parts of a tablet. In some embodiments, the tablet is amulti-layered tablet (e.g., 3-layered tablet).

Referring now to the drawings, FIGS. 1A-1C show the structure, incross-section, of an exemplary unit dosage form 100 according to somerelated embodiments of the invention. Unit dosage form 100 comprises acore 110 and an external layer 120. The embodiments shown in FIGS. 1A-1Cdiffer only in that FIG. 1A shows exemplary embodiments in whichexternal layer 120 covers all of core 110; FIG. 1B shows exemplaryembodiments in which external layer 120 is separated into unconnectedlayers which cover different regions of core 110 (such that externallayer 120 does not cover all of core 110); and FIG. 1C shows exemplaryembodiments in which external layer 120 is a single continuous layerwhich does not cover all of core 110. Unit dosage form 100 is optionallysubstantially rectangular in cross-section (as depicted in FIGS. 1A-1C)along at least one axis. However, the cross-section may have adifferently shape (e.g., substantially circular and/or substantiallyoval), and it is to be understood that the shapes depicted in FIGS.1A-1C are not intended to be limiting.

External layer 120 comprises one or more protease inhibitors and/orantacid compounds, in accordance with any of one of the embodimentsdescribed herein relating to a composition of an external layer, andoptionally consists essentially of one or more protease inhibitorsand/or antacid compounds (e.g., in accordance with one of the respectiveembodiments described herein). Alternatively, external layer 120comprises a combination of one or more excipients with the proteaseinhibitor(s) and/or antacid compound(s) (e.g., in accordance with one ofthe respective embodiments described herein).

In some embodiments, external layer 120 comprises one or more proteaseinhibitors (e.g., in accordance with one of the respective embodimentsdescribed herein), is optionally devoid of antacid compounds, andoptionally consists essentially of one or more protease inhibitors(e.g., in accordance with one of the respective embodiments describedherein). Alternatively, external layer 120 comprises a combination ofone or more excipients with the protease inhibitor(s) (e.g., inaccordance with one of the respective embodiments described herein).

In some embodiments, external layer 120 comprises one or more antacidcompounds (e.g., in accordance with one of the respective embodimentsdescribed herein), is optionally devoid of protease inhibitors, andoptionally consists essentially of one or more antacid compounds (e.g.,in accordance with one of the respective embodiments described herein).Alternatively, external layer 120 comprises a combination of one or moreexcipients with the antacid compound(s) (e.g., in accordance with one ofthe respective embodiments described herein).

In some embodiments, a concentration (as a weight percentage) oftherapeutically active agent in external layer 120 is less than aconcentration of the therapeutically agent in core 110 (e.g., inaccordance with one of the respective embodiments described herein). Insome embodiments, external layer 120 is devoid of the therapeuticallyactive agent.

In some embodiments, a concentration (as a weight percentage) of SNAC inexternal layer 120 is less than a concentration of SNAC in core 110(e.g., in accordance with one of the respective embodiments describedherein). In some embodiments, external layer 120 is devoid of SNAC. Insome embodiments, external layer 120 is devoid of the therapeuticallyactive agent and devoid of SNAC.

FIGS. 2A-2C show the structure, in cross-section, of an exemplary unitdosage form 200 according to some related embodiments of the invention.Unit dosage form 200 as shown in FIGS. 2A-2C, corresponds to unit dosageform 100 (in any one of the respective embodiments described herein) asshown, respectively, in FIGS. 1A-1C, differing from unit dosage form 100in that unit dosage form 200 further comprises coating 230. Unit dosageform 200 comprises a core 210 and an external layer 220, whichcorrespond, respectively, to core 110 and an external layer 120 of unitdosage form 100, as described herein, in any one of the respectiveembodiments.

The embodiments shown in FIGS. 2A-2C differ only in that FIG. 2A showsexemplary embodiments in which external layer 220 covers all of core210; FIG. 2B shows exemplary embodiments in which external layer 220 isseparated into unconnected layers which cover different regions of core210 (such that external layer 220 does not cover all of core 210); andFIG. 2C shows exemplary embodiments in which external layer 220 is asingle continuous layer which does not cover all of core 210.

Unit dosage form 200 is optionally substantially rectangular incross-section (as depicted in FIGS. 2A-2C) along at least one axis.However, the cross-section may have a differently shape (e.g.,substantially circular and/or substantially oval), and it is to beunderstood that the shapes depicted in FIGS. 2A-2C are not intended tobe limiting.

Coating 230 has a composition in accordance with any one of theembodiments described herein relating to a coating, and is optionallyformed from material which dissolves in at least a portion of thegastrointestinal tract (e.g., in accordance with one of the respectiveembodiments described herein).

In some embodiments of any one of the embodiments described herein,coating 230 is an enteric coating, as described herein (e.g., inaccordance with one of the respective embodiments).

In some embodiments of any one of the embodiments described herein,coating 230 dissolves under conditions in the stomach (e.g., inaccordance with one of the respective embodiments described herein),thereby exposing external layer 220. Coating 230 is optionally adaptedfor altering an appearance of unit dosage form 200 (e.g., for aestheticenhancement and/or labeling), to provide flavor and/or mask flavor,and/or to protect external layer 220 and/or core 210 (e.g., frommechanical insult, air, light and/or liquids), e.g., in accordance withone of the respective embodiments described herein).

In some embodiments of any one of the embodiments described herein,coating 230 is an enteric coating (e.g., in accordance with one of therespective embodiments described herein), external layer 220 comprisesone or more protease inhibitors (e.g., in accordance with one of therespective embodiments described herein), and core 210 comprises atherapeutically active agent and SNAC, and optionally one or moreprotease inhibitors (e.g., in accordance with one of the respectiveembodiments described herein). In some such embodiments, unit dosageform 200 is formulated as a tablet (e.g., optionally as depicted in FIG.4).

In embodiments wherein coating 230 is an enteric coating, dissolution ofthe unit dosage form 200 in the gastrointestinal system comprisesdissolution of enteric coating 230 in the intestines, followed primarilyby dissolution of external layer 220, thereby releasing the proteaseinhibitor(s) in the external layer prior to release of therapeuticallyactive agent and SNAC from core 210.

In some of any of the embodiments wherein coating 230 is an entericcoating, external layer 220 and/or core 210 is devoid of an antacid.

In some embodiments of any one of the embodiments described herein,coating 230 is a coating which dissolves under gastric conditions (e.g.,in accordance with one of the respective embodiments described herein),external layer 220 comprises one or more antacid compounds (e.g., inaccordance with one of the respective embodiments described herein), andcore 210 comprises a therapeutically active agent and SNAC, andoptionally one or more antacid compounds (e.g., in accordance with oneof the respective embodiments described herein). In such embodiments,initial dissolution of the unit dosage form 200 in the gastro-intestinaltract primarily comprises dissolution of coating 230 and external layer220 in the stomach, thereby releasing the antacid compound(s) in theexternal layer and reducing an acidity in the stomach (e.g., in avicinity of the unit dosage form) prior to release of therapeuticallyactive agent and SNAC from core 210.

In some embodiments of any one of the embodiments wherein coating 230 isa coating which dissolves under gastric conditions, external layer 220and/or core 210 is devoid of a protease inhibitor.

In some embodiments of any one of the embodiments described herein, unitdosage form 200 is formulated as a coated tablet. In some embodiments,the unit dosage form 200 is formulated as a coated multi-layered tablet(e.g., 3-layered tablet), in which external layer 220 forms an upperlayer and a lower layer, and core 210 is formulated as a middle layersandwiched between the upper layer and a lower layer. An exemplarycoated tablet is shown in FIG. 4. Any of the coated multi-layeredtablets described herein may optionally prepared using any techniqueknown in the art for preparing multi-layered tablets, followed bycoating the tablet using any tablet-coating technique known in the art.

FIG. 3 shows the structure of an exemplary unit dosage form according tosome embodiments of the invention, in a form of tablet 300. Tablet 300comprises a core 310 and an external layer 320, which correspond,respectively, to core 110 and external layer 120 of unit dosage form100, as described herein in any one of the respective embodiments (e.g.,with respect to FIG. 1B).

Tablet 300 is optionally has a substantially circular or substantiallyoval cross-section in cross-section (as depicted in FIG. 3). However,the tablet may have a differently shape, and it is to be understood thatthe shape depicted in FIG. 3 is not intended to be limiting.

External layer 320 includes layer 330 on an obverse face (e.g., acircular or oval face) and layer 340 on a reverse face (e.g., a circularor oval face) of tablet 300. Layers 330 and 340 are optionallyunconnected, such that external layer 320 is separated into twounconnected layers, corresponding to external layer 120 in FIG. 1B).

External layer 320 optionally covers at least 50% of a surface area ofcore 310, optionally at least 60%, optionally at least 70%, optionallyat least 80%, and optionally at least 90% of the surface of core 310.

External layer 320 comprises one or more protease inhibitors and/orantacid compounds, as described for external layer 120 according to anyone of the respective embodiments described herein. In some embodiments,external layer 320 comprises one or more antacid compounds (e.g., inaccordance with one of the respective embodiments described herein).

In some embodiments of any one of the embodiments described herein,external layer 320 is devoid of protease inhibitors. Optionally,external layer 320 consists essentially of one or more antacidcompounds. Alternatively, external layer 320 comprises a combination ofone or more excipients with the antacid compound(s) (e.g., in accordancewith one of the respective embodiments described herein).

In some embodiments of any one of the embodiments described herein,external layer 320 comprises one or more protease inhibitors in additionto one or more antacid compounds (e.g., in accordance with one of therespective embodiments described herein). Optionally, external layer 320consists essentially of one or more protease inhibitors and one or moreantacid compounds. Alternatively, external layer 320 comprises acombination of one or more excipients with the protease inhibitor(s) andantacid compound(s) (e.g., in accordance with one of the respectiveembodiments described herein).

Core 310 comprises the therapeutically active agent of the tablet andSNAC, and optionally further comprises one or more protease inhibitorsand/or antacid compounds, as described for core 110 according to any oneof the respective embodiments described herein. In some embodiments,core 310 comprises one or more antacid compounds (e.g., in accordancewith one of the respective embodiments described herein).

Initial dissolution of tablet 300 in the gastrointestinal systemprimarily comprises dissolution of external layer 320, thereby releasingthe protease inhibitor(s) and/or antacid compound(s) in the externallayer prior to release of the therapeutically active agent and SNAC fromcore 310.

FIG. 4 shows the structure, in cross-section, of an exemplary unitdosage form according to some embodiments of the invention, in a form ofcoated tablet 400. Tablet 400 corresponds to tablet 300 (in any one ofthe respective embodiments described herein), differing in that tablet400 further comprises enteric coating 430. Tablet 400 comprises a core410, an external layer 420, and an enteric coating 430, whichcorrespond, respectively, to core 210, external layer 220 and coating230 of unit dosage form 200, as described herein, in any one of therespective embodiments (e.g., with respect to FIG. 2B).

Enteric coating 430 may optionally be an enteric coating according toany one of the embodiments described herein relating to an entericcoating, for example, with respect to coating 230 (e.g., in accordancewith one of the respective embodiments).

Tablet 400 optionally has a substantially circular or substantially ovalcross-section in cross-section (as depicted in FIG. 4). However, thetablet may have a differently shape, and it is to be understood that theshape depicted in FIG. 4 is not intended to be limiting.

External layer 420 includes layer 440 on an obverse face (e.g., acircular or oval face) and layer 450 on a reverse face (e.g., a circularor oval face) of tablet 400. Layers 440 and 450 are optionallyunconnected, such that external layer 420 is separated into twounconnected layers, corresponding to external layer 220 in FIG. 2B).

External layer 420 optionally covers at least 50% of a surface area ofcore 410, optionally at least 60%, optionally at least 70%, optionallyat least 80%, and optionally at least 90% of the surface of core 410.

External layer 420 comprises one or more protease inhibitors and/orantacid compounds, as described for external layer 120 and/or externallayer 220 according to any one of the respective embodiments describedherein. In some embodiments of any one of the embodiments describedherein, external layer 420 is devoid of antacid compounds. Optionally,external layer 420 consists essentially of one or more proteaseinhibitors. Alternatively, external layer 420 comprises a combination ofone or more excipients with the protease inhibitor(s).

Core 410 comprises the therapeutically active agent of the tablet andSNAC, and optionally further comprises one or more protease inhibitorsand/or antacid compounds, as described for core 110 and/or core 210according to any one of the respective embodiments described herein. Insome embodiments, core 410 comprises one or more protease inhibitors. Insome embodiments, core 410 is devoid of antacid compounds.

Dissolution of tablet 400 in the gastrointestinal system comprisesdissolution of enteric coating 430 in the intestines, followed primarilyby dissolution of external layer 420, thereby releasing the proteaseinhibitor(s) in the external layer prior to release of therapeuticallyactive agent and SNAC from core 410.

FIG. 5 shows a composition of an exemplary external layer 500 accordingto some of any one of the embodiments of the invention. External layer500 corresponds to any external layer described herein (e.g., externallayer 120, 220, 320 and/or 420), in any one of the respectiveembodiments described herein, and has an inner face 510 which faces acore as described herein, and an outer face 520, which faces a coatingdescribed herein and/or surface of a unit dosage device describedherein. External layer 500 comprises a first compound 530 (optionally asingle compound, and optionally a combination of compounds) depicted asrectangles, and a second compound 540 (optionally a single compound, andoptionally a combination of compounds) depicted as circles. Additionalcompounds (not shown) may optionally also be comprised by external layer500.

The distribution of compounds 530 and 540 is optionally inhomogeneous,such that compound 530 is more concentrated in the vicinity of outerface 520 than in the vicinity of inner face 510, and/or compound 540 ismore concentrated in the vicinity of inner face 510 than in the vicinityof outer face 520, as depicted in FIG. 5. Thus, a gradient inconcentration exists between faces 510 and 520. In some embodiments,dissolution of external layer 500 results in dissolution of compound 530preceding dissolution of compound 540.

Alternatively, the distribution of compounds 530 and 540 is homogeneous,such that no gradient in concentration exists between faces 510 and 520.

In some of any of the embodiments described herein, compound 530 is oneor more antacid compounds (e.g., in accordance with one of therespective embodiments described herein), and compound 540 is one ormore protease inhibitor(s) and/or excipient(s) (e.g., in accordance withone of the respective embodiments described herein).

In some of any of the embodiments described herein, compound 530 is oneor more protease inhibitors (e.g., in accordance with one of therespective embodiments described herein), and compound 540 is one ormore antacid compound(s) and/or excipient(s) (e.g., in accordance withone of the respective embodiments described herein).

FIG. 6 shows a composition of an exemplary external layer 600 accordingto some of any one of the embodiments of the invention. External layer600 corresponds to any external layer described herein (e.g., externallayer 120, 220, 320, 420 and/or 520), in any one of the respectiveembodiments described herein, and has an inner face 610 which faces acore as described herein, and an outer face 620, which faces a coatingdescribed herein and/or surface of a unit dosage device describedherein. External layer 600 comprises a first compound 630 (optionally asingle compound, and optionally a combination of compounds) depicted asrectangles, and a second compound 640 (optionally a single compound, andoptionally a combination of compounds) depicted as circles. Additionalcompounds (not shown) may optionally also be comprised by external layer600.

As depicted in FIG. 6, the distribution of compounds 630 and 640 isoptionally inhomogeneous, such that compound 630 is more concentrated inthe vicinity of one or more regions of the unit dosage form surface(e.g., the right-hand side of FIG. 6) than in the vicinity of otherregions of the unit dosage form surface (e.g., the left-hand side ofFIG. 6), and/or compound 540 is more concentrated in the vicinity of oneor more regions of the unit dosage form surface (e.g., the left-handside of FIG. 6) than in the vicinity of other regions of the unit dosageform surface (e.g., the right-hand side of FIG. 6). Thus, a gradient inconcentration exists in the plane of external layer 600.

Alternatively, the distribution of compounds 630 and 640 is homogeneous,such that no gradient in concentration exists in the plane of externallayer 600.

In some of any of the embodiments described herein, compound 630 is oneor more antacid compounds (e.g., in accordance with one of therespective embodiments described herein), and compound 640 is one ormore protease inhibitor(s) and/or excipient(s) (e.g., in accordance withone of the respective embodiments described herein).

In some of any of the embodiments described herein, compound 630 is oneor more protease inhibitors (e.g., in accordance with one of therespective embodiments described herein), and compound 640 is one ormore antacid compound(s) and/or excipient(s) (e.g., in accordance withone of the respective embodiments described herein).

FIG. 7 shows a composition of an exemplary core 700 according to some ofany one of the embodiments of the invention. Core 700 corresponds to anyexternal layer described herein (e.g., core 110, 210, 310 and/or 410),in any one of the respective embodiments described herein, and mayoptionally be combined with any external layer described herein.

As depicted in FIG. 7, the distribution of one or more compounds in core700 is optionally inhomogeneous, such that the one or more compounds areconcentrated within particles 710 separated at least in part by aninterstitial material 720.

Particles 710 optionally comprise the therapeutically active agentand/or SNAC (e.g., in accordance with one of the respective embodimentsdescribed herein), at a concentration which is higher than aconcentration of the therapeutically active agent and/or SNAC ininterstitial material 720. Particles 710 may include different speciesof particles, having different compositions (e.g., one speciescomprising SNAC, and one species comprising a therapeutically activeagent). Particles 710 are optionally in a form of granules and/ormicrospheres.

Interstitial material 720 is optionally devoid of therapeutically activeagent and/or SNAC. Interstitial material 720 optionally comprises on ormore excipients (e.g., in accordance with one of the respectiveembodiments described herein), such as a filler and/or binder, andoptionally consists essentially of one or more excipients.

Alternatively, the distribution of compounds in core 700 is homogeneous.

In some embodiments of any one of the embodiments described herein, atleast 50 weight percents of a core described herein (e.g., any one ofcores 110, 210, 310 and 410) consists of SNAC. In some embodiments, atleast 60 weight percents of a core described herein (e.g., any one ofcores 110, 210, 310 and 410) consists of SNAC. In some embodiments, atleast 70 weight percents of a core described herein (e.g., any one ofcores 110, 210, 310 and 410) consists of SNAC. In some embodiments, atleast 80 weight percents of a core described herein (e.g., any one ofcores 110, 210, 310 and 410) consists of SNAC. In some embodiments, atleast 90 weight percents of a core described herein (e.g., any one ofcores 110, 210, 310 and 410) consists of SNAC.

Without being bound by any particular theory, it is believed thatcompositions (e.g., unit dosage forms and/or cores described herein)having a large proportion of SNAC, which is a salt, tend to be readilysoluble in aqueous solution, including in gastric fluid, as is desirableaccording to some embodiments of the invention.

In some embodiments of any one of the embodiments described herein, theunit dosage form (e.g., any one of unit dosage form 100, unit dosageform 200, and tablet 300) is soluble in gastric fluid. In some suchembodiments, the unit dosage form does not comprise an enteric coating,thereby facilitating dissolution in gastric fluid. In some embodiments,the unit dosage form dissolves in gastric fluid in no more than 60minutes. In some embodiments, the unit dosage form dissolves in gastricfluid in no more than 50 minutes. In some embodiments, the unit dosageform dissolves in gastric fluid in no more than 40 minutes. In someembodiments, the unit dosage form dissolves in gastric fluid in no morethan 30 minutes. In some embodiments, the unit dosage form dissolves ingastric fluid in no more than 20 minutes. In some embodiments, the unitdosage form dissolves in gastric fluid in no more than 15 minutes. Insome embodiments, the unit dosage form dissolves in gastric fluid in nomore than 10 minutes. In some embodiments, the unit dosage formdissolves in gastric fluid in no more than 5 minutes.

In some embodiments of any one of the embodiments described herein, theunit dosage form (e.g., any one of unit dosage form 100, unit dosageform 200, and tablet 300) is not soluble in gastric fluid.

Herein throughout, the phrases “soluble in gastric fluid”, “dissolves ingastric fluid” and the like refer to solubility of a composition insimulated gastric fluid without pepsin, at pH 2.0, under conditionsaccording to USP 23 Apparatus 2 (paddle) (e.g., 800 ml volume, 50rotations per minute). Dissolution is indicated by absence of visiblecomposition at the bottom of the fluid. However, visible materialsuspended in the liquid is not excluded by the terms “soluble” and“dissolution”. The phrase “soluble in gastric fluid” refers herein todissolution within a period of 6 hours. A liquid composition misciblewith simulated gastric fluid is considered herein to be “soluble ingastric fluid”, wherein the dissolution is the mixing of the liquidcomposition with the simulated gastric fluid.

In some embodiments of any one of the embodiments described herein, theunit dosage form is formulated such that absorption of thetherapeutically active agent following oral administration of the unitdosage form is characterized by a bioavailability of the therapeuticallyactive agent which is at least 10% higher than a bioavailability of thetherapeutically active agent following oral administration of a unitdosage form composition consisting of the core of the aforementionedunit dosage form, without the external layer described herein. In someembodiments, the bioavailability is at least 20% higher than (120% ofthe level of) the bioavailability upon oral administration of the core.In some embodiments, the bioavailability is at least 50% higher than(150% of the level of) the bioavailability upon oral administration ofthe core. In some embodiments, the bioavailability is at least twice(200% of the level of) the bioavailability upon oral administration ofthe core. In some embodiments, the bioavailability is at least four-fold(400% of the level of) the bioavailability upon oral administration ofthe core. In some embodiments, the bioavailability is at least ten-fold(1000% of the level of) the bioavailability upon oral administration ofthe core. In some embodiments, the bioavailability is at leasttwenty-fold (2000% of the level of) the bioavailability upon oraladministration of the core.

Without being bound by any particular theory, it is believed that theprotective agent significantly enhances bioavailability by protectingSNAC and thereby increasing the amount of active SNAC which remainsavailable for enhancing absorption of the therapeutically active agent;and/or by protecting the therapeutically active agent and therebyincreasing the amount of therapeutically active agent which remainsactive upon absorption. It is further believed that the protective agentlengthens the period of time during which significant absorption of thetherapeutically active agent occurs (e.g., resulting in a broader peakof plasma levels of the agent as a function of time), by lengthening thetime during which the SNAC and/or therapeutically active agent remainsin active form in the gastrointestinal tract, in addition to increasingthe magnitude of absorption (by enhancing bioavailability).

Compositions Comprising Antacid:

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition for oral administration of atherapeutically active agent, the composition comprising atherapeutically active agent (e.g., as described herein), SNAC and atleast one antacid compound.

In some embodiments, the composition is in a form of a homogeneousmixture, such that the antacid compound is uniformly dispersed among theSNAC and therapeutically active agent (and optionally any additionalingredient present).

In some embodiments, the composition further comprises at least oneprotease inhibitor (e.g., one or more protease inhibitors as describedherein).

In some embodiments, the composition is formulated as a unit dosageform. The unit dosage form may be formulated in any form suitable fororal administration, including solid and/or liquid forms. In someembodiments, the unit dosage form is a solid unit dosage form. In someembodiments, the composition is formulated as a tablet.

In some embodiments, the unit dosage form (e.g., solid unit dosage form)is soluble in gastric fluid. In some embodiments, the unit dosage formdissolves in gastric fluid in no more than 60 minutes. In someembodiments, the unit dosage form dissolves in gastric fluid in no morethan 50 minutes. In some embodiments, the unit dosage form dissolves ingastric fluid in no more than 40 minutes. In some embodiments, the unitdosage form dissolves in gastric fluid in no more than 30 minutes. Insome embodiments, the unit dosage form dissolves in gastric fluid in nomore than 20 minutes. In some embodiments, the unit dosage formdissolves in gastric fluid in no more than 15 minutes. In someembodiments, the unit dosage form dissolves in gastric fluid in no morethan 10 minutes. In some embodiments, the unit dosage form dissolves ingastric fluid in no more than 5 minutes.

In some embodiments, the unit dosage form (e.g., solid unit dosage form)is not soluble in gastric fluid.

In some embodiments of any one of the embodiments described herein, thecomposition consists primarily of the combination of therapeuticallyactive agent, SNAC, and at least one antacid compound described herein,that is, at least 50 weight percents of the composition consists ofingredients selected from the group consisting of a therapeuticallyactive agent, SNAC and at least one antacid compound. In someembodiments, at least 60 weight percents of the composition consists ofa therapeutically active agent, SNAC and at least one antacid compound.In some embodiments, at least 70 weight percents of the compositionconsists of a therapeutically active agent, SNAC and at least oneantacid compound. In some embodiments, at least 80 weight percents ofthe composition consists of a therapeutically active agent, SNAC and atleast one antacid compound. In some embodiments, at least 90 weightpercents of the composition consists of a therapeutically active agent,SNAC and at least one antacid compound. In some embodiments, at least 95weight percents of the composition consists of a therapeutically activeagent, SNAC and at least one antacid compound. In some embodiments, atleast 98 weight percents of the composition consists of atherapeutically active agent, SNAC and at least one antacid compound. Insome embodiments, the composition is formulated as a tablet.

In some embodiments of any one of the embodiments described herein, thecomposition optionally further comprises at least one proteaseinhibitor, and at least 50 weight percents of the composition consistsof ingredients selected from the group consisting of a therapeuticallyactive agent, SNAC, at least one antacid compound and at least oneprotease inhibitor. In some embodiments, at least 60 weight percents ofthe composition consists of a therapeutically active agent, SNAC, atleast one antacid compound and at least one protease inhibitor. In someembodiments, at least 70 weight percents of the composition consists ofa therapeutically active agent, SNAC, at least one antacid compound andat least one protease inhibitor. In some embodiments, at least 80 weightpercents of the composition consists of a therapeutically active agent,SNAC, at least one antacid compound and at least one protease inhibitor.In some embodiments, at least 90 weight percents of the compositionconsists of a therapeutically active agent, SNAC, at least one antacidcompound and at least one protease inhibitor. In some embodiments, atleast 95 weight percents of the composition consists of atherapeutically active agent, SNAC, at least one antacid compound and atleast one protease inhibitor. In some embodiments, at least 98 weightpercents of the composition consists of a therapeutically active agent,SNAC, at least one antacid compound and at least one protease inhibitor.In some embodiments, the composition is formulated as a tablet.

In some embodiments of any one of the embodiments described herein, atleast 50 weight percents the composition consists of SNAC. In someembodiments, at least 60 weight percents of composition consists ofSNAC. In some embodiments, at least 70 weight percents of compositionconsists of SNAC. In some embodiments, at least 80 weight percents ofcomposition consists of SNAC. In some embodiments, at least 90 weightpercents of composition consists of SNAC.

In some embodiments of any one of the embodiments described herein, thecomposition is formulated such that a bioavailability of thetherapeutically active agent upon oral administration of the compositionis at least 10% higher than a bioavailability of the therapeuticallyactive agent upon oral administration of a composition comprising thetherapeutically active agent and SNAC without the at least one antacidcompound (e.g., being identical in all aspects except for the absence ofthe antacid compound(s)). In some embodiments, the bioavailability is atleast 20% higher than (120% of the level of) the bioavailability uponoral administration of a composition comprising the therapeuticallyactive agent and SNAC without the at least one antacid compound. In someembodiments, the bioavailability is at least 50% higher than (150% ofthe level of) the bioavailability upon oral administration of acomposition comprising the therapeutically active agent and SNAC withoutthe at least one antacid compound. In some embodiments, thebioavailability is at least twice (200% of the level of) thebioavailability upon oral administration of a composition comprising thetherapeutically active agent and SNAC without the at least one antacidcompound. In some embodiments, the bioavailability is at least four-fold(400% of the level of) the bioavailability upon oral administration of acomposition comprising the therapeutically active agent and SNAC withoutthe at least one antacid compound. In some embodiments, thebioavailability is at least ten-fold (1000% of the level of) thebioavailability upon oral administration of a composition comprising thetherapeutically active agent and SNAC without the at least one antacidcompound. In some embodiments, the bioavailability is at leasttwenty-fold (2000% of the level of) the bioavailability upon oraladministration of a composition comprising the therapeutically activeagent and SNAC without the at least one antacid compound.

Co-Administration of Antacid with SNAC and Therapeutically EffectiveAgent:

An antacid compound may be utilized advantageously in combination with atherapeutically active agent and SNAC, without necessarily combining allof the ingredients in a single composition.

According to another aspect of embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof, the method comprising co-administering to the subject, anantacid composition comprising at least one antacid compound, as definedherein (e.g., at least one antacid compound described herein), and/or atleast one gastric acid secretion inhibitor; and a composition comprisingthe therapeutically active agent (e.g., as described herein) and SNAC.

As used herein, the phrase “gastric acid secretion inhibitor” refers toany agent which reduces secretion of acid into the stomach, although itdoes not necessarily have any effect on acid which has already beensecreted. Examples of gastric acid secretion inhibitors which may beused in any of the embodiments described herein relating to an antacidcomposition include, without limitation, H₂ receptor antagonists, suchas cimetidine, famotidine, nizatidine and ranitidine; and proton pumpinhibitors, such as omeprazole, lansoprazole, dexlansoprazole,esomeprazole, rabeprazole and ilaprazole.

According to another aspect of embodiments of the invention, there isprovided a use of a composition comprising a therapeutically activeagent and SNAC in the preparation of a medicament for use in thetreatment of a condition treatable by oral administration of thetherapeutically active agent in a subject in need thereof, wherein thetreatment comprises co-administering an antacid composition comprisingat least one antacid compound, as defined herein (e.g., at least oneantacid compound described herein), and/or at least one gastric acidsecretion inhibitor, with the medicament.

According to another aspect of embodiments of the invention, there isprovided a composition comprising a therapeutically active agent andSNAC, for use in the treatment of a condition treatable by oraladministration of the therapeutically active agent in a subject in needthereof, wherein the treatment comprises co-administering an antacidcomposition comprising at least one antacid compound, as defined herein(e.g., at least one antacid compound described herein), and/or at leastone gastric acid secretion inhibitor, with the composition.

In some embodiments of any one of the embodiments described hereinrelating to co-administering an antacid composition, the antacidcomposition is optionally any antacid composition known in the art(e.g., a commercially available antacid composition).

In some embodiments of any one of the embodiments described hereinrelating to co-administering an antacid composition, theco-administering comprises administering the antacid composition priorto or concomitantly with the composition comprising the therapeuticallyactive agent and SNAC.

In some embodiments of any one of the embodiments described hereinrelating to co-administering an antacid composition concomitantly withthe composition comprising the therapeutically active agent and SNAC,the antacid composition comprises at least one antacid compound, asdefined herein (e.g., in accordance with any of the respectiveembodiments described herein).

In some embodiments of any one of the embodiments described hereinrelating to co-administering an antacid composition comprising at leastone gastric acid secretion inhibitor, the co-administering comprisesadministering the antacid composition prior to the compositioncomprising the therapeutically active agent and SNAC (e.g., inaccordance with any of the respective embodiments described herein).

Without being bound by any particular theory, it is believed thatantacid compounds as defined herein (compounds capable of neutralizingstomach acid) are generally effective at reducing acidity in the stomachand/or in a region thereof immediately (as neutralization of acid occursas a relatively rapid chemical reaction) but may have a limitedlong-term effect due to secretion of additional acid into the stomach,and are therefore particularly effective when administered concomitantlywith or shortly (e.g., no more than 90 minutes) prior to the compositioncomprising the therapeutically active agent and SNAC.

It is further believed that gastric acid secretion inhibitors aregenerally effective at reducing stomach acidity for a relatively longduration (due to long-term inhibition of gastric acid secretion) but mayhave a limited effect on acidity immediately after administration due toan absence of a significant effect on acid which is already present inthe stomach, and are therefore particularly effective when administeredprior to the composition comprising the therapeutically active agent andSNAC.

Herein, the term “concomitantly” refers to an events (e.g.,administration of an antacid composition) being within a time period offrom 5 minutes before to 5 minutes after another event (e.g.,administration of a composition comprising a therapeutically activeagent and SNAC), and in some embodiments, within a time period of fromone minute before to one minute after the other event.

In some embodiments, concomitant co-administration is effected byswallowing the two compositions simultaneously.

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition,administering the antacid composition prior to the compositioncomprising the therapeutically active agent and SNAC comprisesadministering the antacid composition no more than 5 days prior to thecomposition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition is administered no more than 4days prior to the composition comprising the therapeutically activeagent and SNAC. In some embodiments, the antacid composition isadministered no more than 3 days prior to the composition comprising thetherapeutically active agent and SNAC. In some embodiments, the antacidcomposition is administered no more than 2 days prior to the compositioncomprising the therapeutically active agent and SNAC. In someembodiments, the antacid composition is administered no more than 1 day(24 hours) prior to the composition comprising the therapeuticallyactive agent and SNAC. In some embodiments, the antacid compositioncomprises a proton-pump inhibitor.

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition, theantacid composition is administered at least about 1 day (e.g., at leastabout 24 hours) prior to the composition comprising the therapeuticallyactive agent and SNAC, for example, from about 1 to about 5 days (e.g.,about 2 days to about 4 days, optionally about 3 days) prior to thecomposition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition comprises a proton-pumpinhibitor.

In some of any of the embodiments described herein in which the antacidcomposition is optionally administered at least 12 hours prior to thecomposition comprising the therapeutically active agent and SNAC, theantacid composition comprises a proton-pump inhibitor.

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition,administering the antacid composition prior to the compositioncomprising the therapeutically active agent and SNAC comprisesadministering the antacid composition no more than 16 hours prior to thecomposition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition is administered no more than12 hours prior to the composition comprising the therapeutically activeagent and SNAC. In some embodiments, the antacid composition isadministered no more than 10 hours prior to the composition comprisingthe therapeutically active agent and SNAC. In some embodiments, theantacid composition is administered no more than 8 hours prior to thecomposition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition is administered no more than 6hours prior to the composition comprising the therapeutically activeagent and SNAC. In some embodiments, the antacid composition isadministered no more than 4 hours prior to the composition comprisingthe therapeutically active agent and SNAC. In some embodiments, theantacid composition comprises an H₂ receptor antagonist.

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition, theantacid composition is administered at least about 2 hours prior to thecomposition comprising the therapeutically active agent and SNAC, forexample, from about 2 to about 10 hours (e.g., 2 to 8 hours, 2 to 6hours, 2 to 4 hours) prior to the composition comprising thetherapeutically active agent and SNAC. In some embodiments, the antacidcomposition comprises an H₂ receptor antagonist or a proton pumpinhibitor, as described herein. In some embodiments, the antacidcomposition comprises an H₂ receptor antagonist, as described herein.

In some of any of the embodiments described herein in which the antacidcomposition is optionally administered at least 2 hours prior to, butless than 12 hours prior to, the composition comprising thetherapeutically active agent and SNAC, the antacid composition comprisesan H₂ receptor antagonist, as described herein.

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition,administering the antacid composition prior to the compositioncomprising the therapeutically active agent and SNAC comprisesadministering the antacid composition no more than 90 minutes prior tothe composition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition is administered no more than60 minutes prior to the composition comprising the therapeuticallyactive agent and SNAC. In some embodiments, the antacid composition isadministered no more than 30 minutes prior to the composition comprisingthe therapeutically active agent and SNAC. In some embodiments, theantacid composition is administered no more than 20 minutes prior to thecomposition comprising the therapeutically active agent and SNAC. Insome embodiments, the antacid composition is administered no more than10 minutes prior to the composition comprising the therapeuticallyactive agent and SNAC. In some embodiments, the antacid compositioncomprises an antacid compound (as defined herein).

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition, thecomposition comprising the therapeutically active agent and SNAC isessentially the same as any one of the compositions described hereincomprising a therapeutically active agent, SNAC and antacid compound(s),with the exception that no antacid compound is present.

In some embodiments, the composition comprising the therapeuticallyactive agent and SNAC and/or the antacid composition further comprisesat least one protease inhibitor (e.g., one or more protease inhibitorsas described herein).

In some embodiments, the composition comprising the therapeuticallyactive agent and SNAC and/or the antacid composition is formulated as aunit dosage form.

The unit dosage form may be formulated in any form suitable for oraladministration, including solid and/or liquid forms. In someembodiments, the unit dosage form (e.g., a unit dosage form of thecomposition comprising the therapeutically active agent and SNAC) is asolid unit dosage form. In some embodiments, the unit dosage form (e.g.,a unit dosage form of the composition comprising the therapeuticallyactive agent and SNAC) is formulated as a tablet.

In some embodiments, the composition comprising the therapeuticallyactive agent and SNAC and the antacid composition (e.g., in solid form)are each soluble in gastric fluid (as defined herein). In someembodiments, the compositions each dissolve in gastric fluid in no morethan 60 minutes. In some embodiments, the compositions each dissolve ingastric fluid in no more than 50 minutes. In some embodiments, thecompositions each dissolve in gastric fluid in no more than 40 minutes.In some embodiments, the compositions each dissolve in gastric fluid inno more than 30 minutes. In some embodiments, the compositions eachdissolve in gastric fluid in no more than 20 minutes. In someembodiments, the compositions each dissolve in gastric fluid in no morethan 15 minutes. In some embodiments, the compositions each dissolve ingastric fluid in no more than 10 minutes. In some embodiments, thecompositions each dissolve in gastric fluid in no more than 5 minutes.

In some embodiments, neither the composition comprising thetherapeutically active agent and SNAC nor the antacid composition (e.g.,in solid form) are soluble in gastric fluid (as defined herein).

In some embodiments of any one of the embodiments described hereinrelating to co-administering at least one antacid composition,absorption of the therapeutically active agent following theco-administration is characterized by a bioavailability of thetherapeutically active agent which is at least 10% higher than abioavailability of the therapeutically active agent following oraladministration of the composition comprising the therapeutically activeagent and SNAC without co-administering the antacid composition. In someembodiments, the bioavailability is at least 20% higher than (120% ofthe level of) the bioavailability without co-administering the antacidcomposition. In some embodiments, the bioavailability is at least 50%higher than (150% of the level of) the bioavailability withoutco-administering the antacid composition. In some embodiments, thebioavailability is at least twice (200% of the level of) thebioavailability without co-administering the antacid composition. Insome embodiments, the bioavailability is at least four-fold (400% of thelevel of) the bioavailability without co-administering the antacidcomposition. In some embodiments, the bioavailability is at leastten-fold (1000% of the level of) the bioavailability withoutco-administering the antacid composition. In some embodiments, thebioavailability is at least twenty-fold (2000% of the level of) thebioavailability without co-administering the antacid composition.

Antacid Compound(s):

Any one or more of the antacid compounds described herein may be used inany one of the embodiments described herein which utilize an antacidcompound.

In some embodiments, the at least one antacid compound is selected fromthe group consisting of calcium carbonate, calcium gluconate, calciumcitrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodiumcitrate, sodium hydroxide, potassium carbonate, potassium bicarbonate,potassium gluconate, potassium citrate, potassium hydroxide, magnesiumcarbonate, magnesium gluconate, magnesium citrate, magnesium oxide andmagnesium hydroxide.

In some embodiments, the at least one antacid compound is selected fromthe group consisting of calcium carbonate, calcium gluconate, sodiumcarbonate, sodium bicarbonate, sodium citrate, sodium hydroxide,potassium carbonate, potassium bicarbonate, potassium citrate, potassiumhydroxide, magnesium carbonate, magnesium hydroxide, magnesium oxide,aluminum carbonate, and aluminum hydroxide.

In some embodiments, the at least one antacid compound the at least oneantacid compound is selected from the group consisting of calciumcarbonate, calcium citrate, sodium bicarbonate, sodium hydroxide,magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesiumoxide, aluminum carbonate, and aluminum hydroxide.

In some embodiments, the at least one antacid compound is selected fromthe group consisting of calcium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, magnesium carbonate, magnesiumhydroxide, magnesium oxide and aluminum hydroxide.

In some embodiments of any one of the embodiments described hereinrelating to an antacid compound, a total amount of antacid compound(s)in a core of a unit dosage form described herein and/or in a unit dosageform described herein, and/or in an antacid composition co-administeredas described herein, is such that the at least one antacid compoundcomprises at least 0.00001 molar equivalent of base. In someembodiments, the at least one antacid compound comprises at least0.00003 molar equivalent of base. In some embodiments, the at least oneantacid compound comprises at least 0.0001 molar equivalent of base. Insome embodiments, the at least one antacid compound comprises at least0.0003 molar equivalent of base. In some embodiments, the at least oneantacid compound comprises at least 0.001 molar equivalent of base. Insome embodiments, the at least one antacid compound comprises at least0.002 molar equivalent of base. In some embodiments, the at least oneantacid compound comprises at least 0.003 molar equivalent of base. Insome embodiments, the at least one antacid compound comprises at least0.005 molar equivalent of base. In some embodiments, the at least oneantacid compound comprises at least 0.01 molar equivalent of base. Insome embodiments, the at least one antacid compound comprises no morethan 0.03 molar equivalent of base.

Herein, 1 molar equivalent of base refers to an amount of a basiccompound (e.g., an antacid compound described herein) capable ofneutralizing 1 mole of HCl (e.g., in an aqueous solution). Indetermining molar equivalents of base in antacid compounds describedherein, each mole of hydroxide ion and/or bicarbonate ion is consideredto be capable of neutralizing 1 mole of HCl, each mole of carbonate ionis considered to be capable of neutralizing 2 moles of HCl, and eachmole of citrate ion (if fully deprotonated) is considered to be capableof neutralizing 3 moles of HCl.

In some embodiments of any one of the embodiments described hereinrelating to an antacid compound, a total amount of antacid compound(s)in a core of a unit dosage form described herein and/or in a unit dosageform described herein, and/or in an antacid composition co-administeredas described herein, is at least 0.5 mg. In some embodiments, the amountof antacid compound(s) is at least 1 mg. In some embodiments, the amountof antacid compound(s) is at least 2 mg. In some embodiments, the amountof antacid compound(s) is at least 5 mg. In some embodiments, the amountof antacid compound(s) is at least 10 mg. In some embodiments, theamount of antacid compound(s) is at least 25 mg. In some embodiments,the amount of antacid compound(s) is at least 50 mg. In someembodiments, the amount of antacid compound(s) is at least 100 mg. Insome embodiments, the amount of antacid compound(s) is at least 200 mg.In some embodiments, the amount of antacid compound(s) is at least 300mg. In some embodiments, the amount of antacid compound(s) is at least400 mg. In some embodiments, the amount of antacid compound(s) is atleast 500 mg.

Protease Inhibitor(s):

In some embodiments of any one of the embodiments described herein, theat least one protease inhibitor included in any of the compositions(including composition unit dosage forms) described herein comprises atleast one trypsin inhibitor. In some embodiments, the at least oneprotease inhibitor consists essentially of one or more trypsininhibitor(s).

Examples of trypsin inhibitor which may be utilized in any one of theembodiments described herein include, without limitation, lima beantrypsin inhibitor, aprotinin, soybean trypsin inhibitor, ovomucoidtrypsin inhibitor and any combination thereof. In some embodiments, theat least one trypsin inhibitor comprises soybean trypsin inhibitor(SBTI). In some embodiments, the at least one trypsin inhibitor (anoptionally the at least one protease inhibitor) consists essentially ofSBTI.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one serpin. In someembodiments, the at least one protease inhibitor consists essentially ofone or more serpin(s).

Examples of serpins which may be utilized in any one of the embodimentsdescribed herein, include, without limitation, alpha 1-antitrypsin,antitrypsin-related protein, alpha 1-antichymotrypsin, kallistatin,protein C inhibitor, cortisol binding globulin, thyroxine-bindingglobulin, angiotensinogen, centerin, protein Z-related proteaseinhibitor, vaspin, monocyte/neutrophil elastase inhibitor, plasminogenactivator inhibitor-2, squamous cell carcinoma antigen-1 (SCCA-1),squamous cell carcinoma antigen-2 (SCCA-2), maspin, proteinase inhibitor6 (PI-6), megsin, serpin B8 (PI-8), serpin B9 (PI-9), bomapin, yukopin,hurpin/headpin, antithrombin, heparin cofactor II, plasminogen activatorinhibitor 1, glia-derived nexin, pigment epithelium derived factor,alpha 2-antiplasmin, complement 1-inhibitor, 47 kDa heat shock protein(HSP47), neuroserpin and pancpin.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one cysteine proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more cysteine protease inhibitor(s).

Examples of cysteine protease inhibitors which may be utilized in anyone of the embodiments described herein include, without limitation,type 1 cystatins, type 2 cystatins, human cystatins C, D, S, SN, and SA,cystatin E/M, cystatin F, and type 3 cystatins (including kininogens).

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one threonine proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more threonine protease inhibitor(s).

Examples of threonine protease inhibitors which may be utilized in anyone of the embodiments described herein include, without limitation,bortezomib, MLN-519, ER-807446 and TMC-95A.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one aspartic proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more aspartic protease inhibitor(s).

Examples of aspartic protease inhibitors which may be utilized in anyone of the embodiments described herein, include, without limitation,α₂-macroglobulin, pepstatin A, aspartic protease inhibitor 11, asparticprotease inhibitor 1, aspartic protease inhibitor 2, aspartic proteaseinhibitor 3, aspartic protease inhibitor 4, aspartic protease inhibitor5, aspartic protease inhibitor 6, aspartic protease inhibitor 7,aspartic protease inhibitor 8, aspartic protease inhibitor 9, pepsininhibitor Dit33, and protease A inhibitor 3.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one metalloproteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more metalloprotease inhibitor(s).

Examples of metalloprotease inhibitors which may be utilized in any oneof the embodiments described herein, include, without limitation,angiotensin-1-converting enzyme inhibitory peptide, antihemorrhagicfactor BJ46a, beta-casein, proteinase inhibitor CeKI, venommetalloproteinase inhibitor DM43, carboxypeptidase A inhibitor, smpl,IMPI, alkaline proteinase, latexin, carboxypeptidase inhibitor,antihemorrhagic factor HSF, testican-3, SPOCK3, TIMP1, metalloproteinaseinhibitor 1, metalloproteinase inhibitor 2, TIMP2, metalloproteinaseinhibitor 3, TIMP3, metalloproteinase inhibitor 4, TIMP4, putativemetalloproteinase inhibitor tag-225, tissue inhibitor ofmetalloprotease, WAP, kazal inhibitor, immunoglobulin, and kunitz andNTR domain-containing protein 1.

Examples of protease inhibitors which may be utilized in any one of theembodiments described herein also include, without limitation,AEBSF-HCl, ε-aminocaproic acid, α1-antichymotypsin, antipain,antithrombin III, α1-antitrypsin, APMSF (4-amidinophenyl-methanesulfonyl-fluoride), sprotinin, benzamidine, chymostatin, DFP(diisopropylfluoro-phosphate), leupeptin,4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride, PMSF(phenylmethyl sulfonyl fluoride), TLCK(1-chloro-3-tosylamido-7-amino-2-heptanone), TPCK(1-chloro-3-tosylamido-4-phenyl-2-butanone), pentamidine isothionate,pepstatin, guanidium, α2-macroglobulin, a chelating agent of zinc, andiodoacetate.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is at least about 0.1 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 0.2 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 0.3 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 0.4mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 0.6 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 0.8 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 1 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 1.5mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 2 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 2.5 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 3 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 5 mg.In some embodiments, the amount of a protease inhibitor in a unit dosageform described herein is at least about 7 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 10 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 12mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 15 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 20 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 30 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 50mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 70 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 100 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 0.1 to 1 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 0.2 to 1 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 0.3 to 1 mg. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is in a range of from 0.5 to 1 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 0.1 to 2 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 0.2 to 2 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 0.3 to 2 mg. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is in a range of from 0.5 to 2 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 1 to 2 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 1 to 10 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 2 to 10 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 3 to 10 mg. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is in a range of from 5 to 10 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 1 to 20 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 2 to 20 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 3 to 20 mg. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is in a range of from 5 to 20 mg. In some embodiments, the amountof a protease inhibitor in a unit dosage form described herein is in arange of from 10 to 20 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 10 to 100 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 20 to 100 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 30 to 100 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 50 to 100 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 10 to 200 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 20 to 200 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 30 to 200 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 50 to 200 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is in a range of from 100 to 200 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of a protease inhibitor in aunit dosage form described herein is at least about 10 kallikreininactivator units (k.i.u.). In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is at leastabout 12 k.i.u. In some embodiments, the amount of a protease inhibitorin a unit dosage form described herein is at least about 15 k.i.u. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is at least about 20 k.i.u. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is at least about 30 k.i.u. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is at leastabout 40 k.i.u. In some embodiments, the amount of a protease inhibitorin a unit dosage form described herein is at least about 50 k.i.u. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is at least about 70 k.i.u. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is at least about 100 k.i.u. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is at leastabout 150 k.i.u. In some embodiments, the amount of a protease inhibitorin a unit dosage form described herein is at least about 200 k.i.u. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is at least about 300 k.i.u. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is at least about 500 k.i.u. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is at leastabout 700 k.i.u. In some embodiments, the amount of a protease inhibitorin a unit dosage form described herein is at least about 1000 k.i.u. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is at least about 1500 k.i.u. In some embodiments,the amount of a protease inhibitor in a unit dosage form describedherein is at least about 3000 k.i.u. In some embodiments, the amount ofa protease inhibitor in a unit dosage form described herein is at leastabout 4000 k.i.u. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 5000k.i.u.

Herein and in the art, a “kallikrein inactivating unit” (k.i.u) refersto an amount of protease inhibitor that has the ability to inhibit 2units of kallikrein by 50% (e.g., in aqueous solution at an optimal pHand solution volume for activity of the protease inhibitor).

In some embodiments of any one of the embodiments described hereinrelating to a composition and/or unit dosage form comprising a proteaseinhibitor and therapeutically active agent, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 1:1 to5:1 (protease inhibitor: therapeutically active agent). In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1. In some embodiments, aweight ratio of protease inhibitor to therapeutically active agent is ina range of from 10:1 to 20:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from20:1 to 30:1. In some embodiments, a weight ratio of protease inhibitorto therapeutically active agent is in a range of from 30:1 to 40:1. Insome embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 40:1 to 50:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 50:1 to 75:1. In some embodiments, aweight ratio of protease inhibitor to therapeutically active agent is ina range of from 75:1 to 100:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from100:1 to 200:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 300:1 to 400:1. Insome embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 400:1 to 500:1. Insome embodiments, the protease inhibitor is soybean trypsin inhibitor.

SNAC:

In some embodiments of any one of the embodiments described herein, theSNAC may optionally be replaced with a similar compound, such as SNAD(sodium 10-N-(2-hydroxybenzoyl)aminodecanoic acid). As shown below, thestructure of SNAD differs from that of SNAC only in the length of thefatty acid moiety.

In some embodiments of any one of the embodiments described herein, theSNAC may optionally be replaced with a similar compound, wherein thecaprylic acid moiety of SNAC is replaced by another fatty acid moiety atleast 6 carbon atoms in length, for example, from 6 to 20 carbon atomsin length, optionally from 6 to 18 carbon atoms in length, optionallyfrom 6 to 16 carbon atoms in length, optionally from 6 to 14 carbonatoms in length, optionally from 6 to 12 carbon atoms in length andoptionally from 6 to 10 carbon atoms in length. The fatty acid moietymay be saturated (e.g., as are caprylic acid in SNAC and decanoic acidin SNAD) or unsaturated (i.e., comprising at least one unsaturatedcarbon-carbon bond).

In some embodiments of any one of the embodiments described herein, aconcentration of SNAC in a composition described herein or in a core ofa unit dosage form described herein is in a range of from 2.5 to 99.4weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 2.5 to 10 weight percents.In some of the aforementioned embodiments, the concentration of SNAC isin a range of from 8 to 15 weight percents. In some of theaforementioned embodiments, the concentration of SNAC is in a range offrom 10 to 20 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 15 to 30weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 20 to 40 weight percents. Insome of the aforementioned embodiments, the concentration of SNAC is ina range of from 30 to 50 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 40 to 60weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 50 to 70 weight percents. Insome of the aforementioned embodiments, the concentration of SNAC is ina range of from 2.5 to 10 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 2.5 to 10weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 70 to 99.4 weight percents.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to the therapeutically active agent in acomposition described herein or in a core of a unit dosage formdescribed herein is in a range of from 5:1 to 10:1 (SNAC:therapeutically active agent). In some embodiments, the ratio is about7.5:1. In some embodiments, the composition or core further comprises aprotease inhibitor. In some of the aforementioned embodiments whereinthe composition comprises a protease inhibitor, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from1:1 to 5:1 (protease inhibitor: therapeutically active agent),optionally about 3:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 5:1 to10:1, optionally about 7.5:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from10:1 to 20:1, optionally about 15:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 20:1 to 30:1, optionally about 25:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 30:1 to 40:1, optionally about 35:1. In some embodiments,a weight ratio of protease inhibitor to therapeutically active agent isin a range of from 40:1 to 50:1, optionally about 45:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 50:1 to 75:1, optionally about62.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 75:1 to 100:1,optionally about 87.5:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 100:1 to200:1, optionally about 150:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from200:1 to 300:1, optionally about 250:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 300:1 to 400:1, optionally about 350:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 400:1 to 500:1, optionally about450:1. In some embodiments, the protease inhibitor is soybean trypsininhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 10:1 to 20:1 (SNAC: therapeutically active agent). Insome embodiments, the ratio is about 15:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 20:1 to 30:1 (SNAC: therapeutically active agent). Insome embodiments, the ratio is about 25:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 30:1 to 50:1 (SNAC: therapeutically active agent). Insome embodiments, the ratio is about 40:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 50:1 to 100:1 (SNAC: therapeutically active agent).In some embodiments, the ratio is about 75:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 100:1 to 200:1 (SNAC: therapeutically active agent).In some embodiments, the ratio is about 150:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 200:1 to 300:1 (SNAC: therapeutically active agent).In some embodiments, the ratio is about 250:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 300:1 to 500:1 (SNAC: therapeutically active agent).In some embodiments, the ratio is about 400:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent in a compositiondescribed herein or in a core of a unit dosage form described herein isin a range of from 500:1 to 1000:1 (SNAC: therapeutically active agent).In some embodiments, the ratio is about 750:1. In some embodiments, thecomposition or core further comprises a protease inhibitor. In some ofthe aforementioned embodiments wherein the composition comprises aprotease inhibitor, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 1:1 to 5:1 (proteaseinhibitor: therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.1 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about0.2 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.3 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about0.4 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.6 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about0.8 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 1 mg. In some embodiments, the amountof SNAC in a unit dosage form described herein is at least about 1.5 mg.In some embodiments, the amount of SNAC in a unit dosage form describedherein is at least about 2 mg. In some embodiments, the amount of SNACin a unit dosage form described herein is at least about 2.5 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 3 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 5 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 7 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 10 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 12 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 15 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 20 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 30 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 50 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 70 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 100 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 0.1 to 1 mg. In some embodiments,the amount of SNAC in a unit dosage form described herein is in a rangeof from 0.2 to 1 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 0.3 to 1 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 0.5 to 1 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 0.1 to 2 mg. In some embodiments,the amount of SNAC in a unit dosage form described herein is in a rangeof from 0.2 to 2 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 0.3 to 2 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 0.5 to 2 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 1 to 2mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 1 to 10 mg. In some embodiments,the amount of SNAC in a unit dosage form described herein is in a rangeof from 2 to 10 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 3 to 10 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 5 to 10 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 1 to 20 mg. In some embodiments,the amount of SNAC in a unit dosage form described herein is in a rangeof from 2 to 20 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 3 to 20 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 5 to 20 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 10 to20 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 100 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 100 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to100 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 100 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 200 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 200 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to200 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 200 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 100 to 200 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 500 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 500 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to500 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 500 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 100 to 500 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 200 to500 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 1000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 1000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to1000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 1000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 100 to 1000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 200 to1000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 500 to 1000 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 1000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 1000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to1000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 1000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 100 to 1000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 200 to1000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 500 to 1000 mg.

In some embodiments of any one of the embodiments described hereinrelating to a unit dosage form, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 2000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 20 to 2000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 30 to2000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 50 to 2000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 100 to 2000 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 200 to2000 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 500 to 2000 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 1000 to 2000 mg.

In some embodiments of any one of the embodiments described hereinrelating to an amount of SNAC in a unit dosage form, the amount oftherapeutically active agent is in accordance with any one of the ratiosof SNAC to therapeutically active agent described herein. In someembodiments, the unit dosage form further comprises at least oneprotease inhibitor in an amount which is in accordance with any one ofthe ratios of protease inhibitor to therapeutically active agentdescribed herein.

Therapeutically Active Agent:

In some embodiments of any one of the embodiments described herein, theunit dosage form according to any one of the aspects described hereincomprises at least 50 μg of therapeutically active agent. In someembodiments, the unit dosage form comprises at least 100 μg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises at least 200 μg of therapeutically active agent. In someembodiments, the unit dosage form comprises at least 500 μg oftherapeutically active agent. In some embodiments, the amount of SNAC isin accordance with any one of the ratios of SNAC to therapeuticallyactive agent described herein. In some embodiments, the unit dosage formfurther comprises at least one protease inhibitor in an amount which isin accordance with any one of the ratios of protease inhibitor totherapeutically active agent described herein.

In some embodiments of any one of the embodiments described herein, theunit dosage form according to any one of the aspects described hereincomprises 2000 μg or less of therapeutically active agent. In someembodiments, the unit dosage form comprises 1000 μg or less oftherapeutically active agent. In some embodiments, the amount of SNAC isin accordance with any one of the ratios of SNAC to therapeuticallyactive agent described herein. In some embodiments, the unit dosage formfurther comprises at least one protease inhibitor in an amount which isin accordance with any one of the ratios of protease inhibitor totherapeutically active agent described herein.

In some embodiments of any one of the embodiments described herein, theunit dosage form comprises from 200 to 2000 μg of therapeutically activeagent. In some embodiments, the unit dosage form comprises from 500 to1000 μg of therapeutically active agent. In some embodiments, the unitdosage form comprises about 750 μg of therapeutically active agent. Insome embodiments, the therapeutically active agent is a parathyroidhormone or a fragment thereof. In some embodiments, the therapeuticallyactive agent is teriparatide. In some embodiments, the amount of SNAC isin accordance with any one of the ratios of SNAC to therapeuticallyactive agent described herein. In some embodiments, the unit dosage formfurther comprises at least one protease inhibitor in an amount which isin accordance with any one of the ratios of protease inhibitor totherapeutically active agent described herein.

Compositions described herein are particularly suitable for enhancingthe absorption of therapeutically active agents whose absorption uponoral administration is limited, for example, by a large molecularweight, strong hydrophilicity (e.g., which inhibits crossing of lipidmembranes in the gastrointestinal tract), strong lipophilicity (e.g.,which reduces diffusion in the gastrointestinal tract, inhibitspermeation of hydrophilic layers such as intestinal mucus linings and/orresults in accumulation in lipid membranes), and/or degradation in thegastrointestinal tract (e.g., by proteolysis).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent included in any of the compositions(including composition unit dosage forms) described herein has amolecular weight of at least 0.5 kDa. In some embodiments, the molecularweight is in a range of from 0.5 to 150 kDa. In some embodiments, themolecular weight is in a range of from 0.5 to 100 kDa. In someembodiments, the molecular weight is in a range of from 0.5 to 75 kDa.In some embodiments, the molecular weight is in a range of from 0.5 to50 kDa. In some embodiments, the molecular weight is in a range of from0.5 to 30 kDa. In some embodiments, the molecular weight is in a rangeof from 0.5 to 20 kDa. In some embodiments, the molecular weight is in arange of from 0.5 to 10 kDa. In some embodiments, the molecular weightis in a range of from 0.5 to 7.5 kDa. In some embodiments, the molecularweight is in a range of from 0.5 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 1 kDa.In some embodiments, the molecular weight is in a range of from 1 to 150kDa. In some embodiments, the molecular weight is in a range of from 1to 100 kDa. In some embodiments, the molecular weight is in a range offrom 1 to 75 kDa. In some embodiments, the molecular weight is in arange of from 1 to 50 kDa. In some embodiments, the molecular weight isin a range of from 1 to 30 kDa. In some embodiments, the molecularweight is in a range of from 1 to 20 kDa. In some embodiments, themolecular weight is in a range of from 1 to 10 kDa. In some embodiments,the molecular weight is in a range of from 1 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 1 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 2 kDa.In some embodiments, the molecular weight is in a range of from 2 to 150kDa. In some embodiments, the molecular weight is in a range of from 2to 100 kDa. In some embodiments, the molecular weight is in a range offrom 2 to 75 kDa. In some embodiments, the molecular weight is in arange of from 2 to 50 kDa. In some embodiments, the molecular weight isin a range of from 2 to 30 kDa. In some embodiments, the molecularweight is in a range of from 2 to 20 kDa. In some embodiments, themolecular weight is in a range of from 2 to 10 kDa. In some embodiments,the molecular weight is in a range of from 2 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 2 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 3 kDa.In some embodiments, the molecular weight is in a range of from 3 to 150kDa. In some embodiments, the molecular weight is in a range of from 3to 100 kDa. In some embodiments, the molecular weight is in a range offrom 3 to 75 kDa. In some embodiments, the molecular weight is in arange of from 3 to 50 kDa. In some embodiments, the molecular weight isin a range of from 3 to 30 kDa. In some embodiments, the molecularweight is in a range of from 3 to 20 kDa. In some embodiments, themolecular weight is in a range of from 3 to 10 kDa. In some embodiments,the molecular weight is in a range of from 3 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 3 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 4 kDa.In some embodiments, the molecular weight is in a range of from 4 to 150kDa. In some embodiments, the molecular weight is in a range of from 4to 100 kDa. In some embodiments, the molecular weight is in a range offrom 4 to 75 kDa. In some embodiments, the molecular weight is in arange of from 4 to 50 kDa. In some embodiments, the molecular weight isin a range of from 4 to 30 kDa. In some embodiments, the molecularweight is in a range of from 4 to 20 kDa. In some embodiments, themolecular weight is in a range of from 4 to 10 kDa. In some embodiments,the molecular weight is in a range of from 4 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 4 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 5 kDa.In some embodiments, the molecular weight is in a range of from 5 to 150kDa. In some embodiments, the molecular weight is in a range of from 5to 100 kDa. In some embodiments, the molecular weight is in a range offrom 5 to 75 kDa. In some embodiments, the molecular weight is in arange of from 5 to 50 kDa. In some embodiments, the molecular weight isin a range of from 5 to 30 kDa. In some embodiments, the molecularweight is in a range of from 5 to 20 kDa. In some embodiments, themolecular weight is in a range of from 5 to 10 kDa. In some embodiments,the molecular weight is in a range of from 5 to 7.5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 10 kDa.In some embodiments, the molecular weight is in a range of from 10 to150 kDa. In some embodiments, the molecular weight is in a range of from10 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 10 to 75 kDa. In some embodiments, the molecular weight is in arange of from 10 to 50 kDa. In some embodiments, the molecular weight isin a range of from 10 to 30 kDa. In some embodiments, the molecularweight is in a range of from 10 to 20 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 20 kDa.In some embodiments, the molecular weight is in a range of from 20 to150 kDa. In some embodiments, the molecular weight is in a range of from20 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 20 to 75 kDa. In some embodiments, the molecular weight is in arange of from 20 to 50 kDa. In some embodiments, the molecular weight isin a range of from 20 to 30 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 50 kDa.In some embodiments, the molecular weight is in a range of from 50 to150 kDa. In some embodiments, the molecular weight is in a range of from50 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 50 to 75 kDa.

Without being bound by any particular theory, it is believed that agentshaving a relatively high molecular weight (e.g., at least 0.5 kDa, atleast 1 kDa, at least 2 kDa, at least 3 kDa, at least 4 kDa) tend to beless efficiently absorbed upon oral administration than relatively smallmolecules (e.g., molecules having a molecular weight of less than 0.5kDa, or less than 1 kDa) and therefore, their absorption is particularlysusceptible to enhancement by SNAC activity.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent included in any of the compositions(including composition unit dosage forms) described herein is a hormoneand/or cytokine (e.g., a hormone). In some embodiments, the polypeptideis a polypeptide hormone and/or cytokine, or a fragment thereof (e.g., afragment exhibiting an activity of the hormone and/or cytokine), or ahomolog of a polypeptide hormone and/or cytokine or fragment thereof.

Examples of polypeptides which may be utilized (per se or as fragmentsthereof and/or homologs thereof) as therapeutically active agentsaccording to embodiments of the invention include, without limitation,insulin, a glucagon, a parathyroid hormone, an interferon, a growthhormone, an erythropoietin, a calcitonin, an omentin, a motilin, aleptin, a peptide YY, a GLP-1 (glucagon-like peptide-1), a GLP-2(glucagon-like peptide-2), granulocyte-colony stimulating factor(G-CSF), an antibody (e.g., monoclonal antibody), an interleukin, anerythropoietin, a vasopressin, a vasoactive intestinal peptide, apituitary adenylate cyclase-activating peptide (PACAP), a blood clottingfactor, an endomorphin (e.g., endomorphin-1, endomorphin-2), a TNFinhibitor (e.g., infliximab, adalimumab, certolizumab, golimumab,etanercept), disitertide, octreotide (a somatotropin analog),davunetide, icatibant, glucocerebrosidase, a gonadotropin releasinghormone (GnRH), acyline (a GnRH antagonist), and a GLP-1 agonist such asexendin-4 (including exenatide and lixisenatide). Examples of growthhormones, include, without limitation, somatotropin (growth hormone 1),growth hormone 2, and growth factors (e.g., insulin-like growth factor 1(IGF-1), fibroblast growth factor (FGF), ciliary neurotrophic factor).

Insulin, glucagon, parathyroid hormone, erythropoietin, calcitonin,motilin, leptin, peptide YY, GLP-1 (including derivatives thereof suchas liraglutide, taspoglutide, albiglutide and dulaglutide), GLP-2, GnRH(including derivatives thereof such as leuprorelin, buserelin,histrelin, goserelin, deslorelin, nafarelin and triptorelin), vasopressin (including derivatives thereof such as desmopres sin), vasoactiveintestinal peptide (including aviptadil), pituitary adenylatecyclase-activating peptide (PACAP), growth hormones (including axokine,a homolog of a fragment of ciliary neurotrophic factor) and G-CSF arenon-limiting examples of polypeptide hormones.

Interferons, interleukins, erythropoietin and analogs thereof (e.g.,darbepoetin), omentin and G-CSF are non-limiting examples of polypeptidecytokines.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is parathyroid hormone (PTH) or a fragmentthereof (e.g., a fragment exhibiting an activity of PTH). In someembodiments, the polypeptide is teriparatide (i.e., a PTH fragmenthaving amino acid residues 1-34 of PTH).

Herein, the term “parathyroid hormone” or its abbreviation “PTH”encompasses parathyroid hormone (having a naturally occurring amino acidsequence, e.g., in humans) and homologs of the parathyroid hormone. A“fragment” of parathyroid hormone encompasses fragments of parathyroidhormone having a naturally occurring amino acid sequence (e.g., inhumans) and homologs of such fragments.

Without being bound by any particular theory, it is believed that agentswhich are polypeptides tend to be poorly absorbed upon oraladministration, for example, due to their polarity and/or relativelylarge molecular weight; and therefore, their absorption is particularlysusceptible to enhancement by SNAC activity.

In some embodiments of any one of the embodiments described hereinwherein the therapeutically active agents is a polypeptide, thecomposition further comprises at least one protease inhibitor, forexample, according to any one of the embodiments described hereinrelating to a protease inhibitor.

It has been reported that therapeutically active agents which exhibitmore than one of the following criteria tend to be poorly absorbed uponoral administration (when administered alone), a phenomenon referred toin the art as “Lipinski's rule of 5”:

-   -   (i) a total number of nitrogen-hydrogen bonds and oxygen        hydrogen bonds (which are typically hydrogen bond donors) which        is more than 5;    -   (ii) a total number of nitrogen and oxygen atoms (which are        typically hydrogen bond acceptors) which is more than 5;    -   (iii) an octanol-water partition coefficient (log P) which is        greater than 5; and/or    -   (iv) a molecular weight of at least 500 Da (0.5 kDa).

The abovementioned criteria (i) and (ii) are associated with hydrogenbonding and hydrophilicity; whereas criteria (iii) is associated withlipophilicity.

As described herein, therapeutically active agents poorly absorbed uponoral administration when administered alone are particularly suitablefor being included in compositions described herein, in order to enhancetheir absorption.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent meets at least one of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets at least two of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets at least three of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets all four of the abovementionedcriteria (i), (ii), (iii) and (iv).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 0.5 kDa,in accordance with any one of the embodiments described herein relatingto a molecular weight of at least 0.5 kDa, and further meets at leastone of the abovementioned criteria (i), (ii) and (iii). In some suchembodiments, the therapeutically active agent meets at least two of theabovementioned criteria (i), (ii) and (iii).

Dihydroergotamine and fondaparinux are non-limiting examples ofnon-peptidic agents having a molecular weight of at least 0.5 kDa, whichare poorly absorbed upon oral administration.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of less than 0.5kDa, and meets at least one of the abovementioned criteria (i), (ii) and(iii). In some such embodiments, the therapeutically active agent meetsat least two of the abovementioned criteria (i), (ii) and (iii). In somesuch embodiments, the therapeutically active agent meets all three ofthe abovementioned criteria (i), (ii) and (iii).

In addition, ionic molecules tend to be poorly absorbed upon oraladministration, generally due to a considerably reduced ability to crosslipid membranes. Whether a molecule is ionic or non-ionic often dependson pH, which varies according to location in the gastrointestinal tract.In general, it is believed that the more a therapeutically active agentis in ionic form in the gastrointestinal tract, the more likely it is tobe poorly absorbed upon oral administration.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of7.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of6.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of5.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of4.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of3.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of2.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of1.0.

Examples of such agents include, without limitation, compoundscomprising at least one basic group (e.g., amine group) which ispositively charged at a pH of 7.0 (or less).

Herein, a compound is considered “ionic” when it comprises at least onefunctional group which is charged in at least 50% of the molecules in apopulation of molecules of the compound under designated conditions(e.g., in an aqueous solution at a designated pH value or range of pHvalues). The skilled person will be readily capable of determiningwhether a functional group is charged in at least 50% of the molecules,for example, by determining a pKa value associated with the functionalgroup. An ionic compound, as defined herein, may optionally have a netnegative charge, optionally a net positive charge, and optionally anequal number of negatively charged functional groups and positivelyfunctional groups, resulting in no net charge.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 5.0 to 7.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 5.0 to 8.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 4.0 to 9.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 3.0 to 10.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 2.0 to 11.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic at a pH value and/or rangeaccording to any one of the abovementioned embodiments, and further hasa molecular weight of at least 0.5 kDa, in accordance with any one ofthe embodiments described herein relating to a molecular weight of atleast 0.5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic at a pH value and/or rangeaccording to any one of the abovementioned embodiments, and further hasa molecular weight of less than 0.5 kDa.

Examples of ionic therapeutically active agents which tend to have amolecular weight of less than 0.5 kDa, and which tend to exhibit poorabsorption upon oral administration, include, without limitation,bisphosphonates (e.g., for use in treating osteoporosis and relatedconditions) such as alendronate, clodronate, etidronate, ibandronate,neridronate, olpadronate, pamidronate, risedronate, tiludronate andzoledronate; and cromolyn (e.g., cromolyn sodium).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a Class III agent according to theBiopharmaceutics Classification System (BCS), as provided by the U.S.FDA, that is, the therapeutically active agent is characterized by lowpermeability and high solubility.

In the context of the BCS, the phrase “low permeability” refers hereinand in the art to absorption of less than 90% of a given agent upon oraladministration in humans (in the absence of SNAC), as determined bymass-balance determination and/or in comparison to an intravenous dose.

In some embodiments, absorption of a Class III therapeutically activeagent is less than 50% upon oral administration (in the absence ofSNAC). In some embodiments, absorption is less than 20% upon oraladministration (in the absence of SNAC). In some embodiments, absorptionis less than 10% upon oral administration (in the absence of SNAC). Insome embodiments, absorption is less than 5% upon oral administration(in the absence of SNAC). In some embodiments, absorption is less than2% upon oral administration (in the absence of SNAC). In someembodiments, absorption is less than 1% upon oral administration (in theabsence of SNAC).

In the context of the BCS, the phrase “high solubility” refers hereinand in the art to an amount of therapeutically active agent in anadministered dose being soluble in 250 ml or less of water over a pHrange of 1 to 7.5.

Formulation of Compositions:

Each of the compositions and unit dosage forms described herein,including cores and external layers described herein (individually or incombination), optionally consist essentially of the functionalingredients described hereinabove (e.g., a therapeutically active agent,SNAC, protease inhibitor(s) and/or antacid compound(s)), oralternatively, the composition further comprises suitablepharmaceutically acceptable carriers and/or excipients.

Hereinafter, the phrases “physiologically acceptable carrier” and“pharmaceutically acceptable carrier”, which may be interchangeablyused, refer to a carrier or a diluent that does not cause significantirritation to an organism and does not abrogate the activity (e.g.,biological activity) and properties of the functional ingredient (e.g.,a therapeutically active agent). An adjuvant is included under thesephrases.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of anactive ingredient. Examples, without limitation, of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils and polyethyleneglycols.

The term “unit dosage form”, as used herein, describes physicallydiscrete units, each unit containing a predetermined quantity of one ormore active ingredient(s) calculated to produce the desired therapeuticeffect, in association with at least one pharmaceutically acceptablecarrier, diluent, excipient, or combination thereof.

In some embodiments of any one of the embodiments described herein, thecomposition is formulated as a solid composition. In some embodiments,the composition is formulated as a tablet.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

Pharmaceutical compositions and unit dosage forms of some embodiments ofthe invention, including cores and external layers described herein(individually or in combination), may be manufactured by processes wellknown in the art, e.g., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes.

Pharmaceutical compositions and unit dosage forms for use in accordancewith some embodiments of the invention, including cores and externallayers described herein (individually or in combination), may thus beformulated in conventional manner using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries, whichfacilitate processing of the active ingredients into preparations which,can be used pharmaceutically.

The pharmaceutical composition and unit dosage forms can be formulatedreadily by combining the active compounds with pharmaceuticallyacceptable carriers well known in the art as being suitable for oraladministration. Such carriers optionally facilitate formulation of thepharmaceutical composition as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions, and the like, for oralingestion by a patient. Pharmacological preparations for oral use can bemade using a solid excipient, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries if desired, to obtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/orphysiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrating agents may be added, such as cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate; and/or lubricants such as talc or magnesium stearate.

In some embodiments of any one of the embodiments described herein, anyone of the compositions or unit dosage forms described herein (e.g.,formulated as a tablet) further comprises a lubricant. In someembodiments, the lubricant is included in a concentration of 5 weightpercents or less, optionally 2 weight percents or less, and optionallyabout 1 weight percent. In some embodiments, the composition or unitdosage form described herein (e.g., formulated as a tablet) consistsessentially of the therapeutically active agent (as described herein),SNAC, lubricant and least one protective agent (as described herein). Insome embodiments, the lubricant is magnesium stearate.

Dragee cores are optionally provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, titanium dioxide, lacquer solutions and suitableorganic solvents or solvent mixtures. Dyestuffs or pigments may be addedto the tablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive ingredients may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

Pharmaceutical compositions suitable for use in context of someembodiments of the invention include compositions wherein thetherapeutically active agent is contained in an amount effective toachieve the intended purpose. More specifically, the compositionpreferably comprises a therapeutically effective amount oftherapeutically active agent, that is, an amount of therapeuticallyactive agent effective to prevent, alleviate or ameliorate symptoms of adisorder or prolong the survival of the subject being treated.Furthermore, an amount of SNAC is preferably effective for enhancingabsorption of the therapeutically active agent (e.g., in a mannerdescribed herein); and an amount of protease inhibitor is preferablyeffective for inhibiting degradation of the therapeutically active agent(e.g., a polypeptide agent) by a protease.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any preparation used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromin vitro and cell culture assays. For example, a dose can be formulatedin animal models to achieve a desired concentration or titer. Suchinformation can be used to more accurately determine useful doses inhumans.

Toxicity and therapeutic efficacy of the therapeutically active agentdescribed herein can be determined by standard pharmaceutical proceduresin vitro, in cell cultures or experimental animals. The data obtainedfrom these in vitro and cell culture assays and animal studies can beused in formulating a range of dosage for use in human. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation and dosage can be chosenby the individual physician in view of the patient's condition. (Seee.g., Fingl et al., 1975, in “The Pharmacological Basis ofTherapeutics”, Ch. 1 p. 1).

Dosage amount and interval may be adjusted individually to providelevels (e.g., plasma levels) of the therapeutically active agentsufficient to induce or suppress a biological effect (minimal effectiveconcentration, MEC). The MEC will vary for each preparation, but can beestimated from in vitro data. Dosages necessary to achieve the MEC willdepend on individual characteristics. Detection assays can be used todetermine plasma concentrations.

Depending on the severity and responsiveness of the condition to betreated, dosing can be of a single or a plurality of administrations,with course of treatment lasting from several hours to several weeks oruntil cure is effected or diminution of the disease state is achieved.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

Compositions of some embodiments of the invention may, if desired, bepresented in a pack or dispenser device, such as an FDA approved kit,which may contain one or more unit dosage forms containing the activeingredient. The pack may, for example, comprise metal or plastic foil,such as a blister pack. The pack or dispenser device may be accompaniedby instructions for administration. The pack or dispenser may also beaccommodated by a notice associated with the container in a formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the compositions or human or veterinaryadministration. Such notice, for example, may be of labeling approved bythe U.S. Food and Drug Administration for prescription drugs or of anapproved product insert. Compositions comprising a preparation of theinvention may also be prepared (e.g., as described herein), placed in anappropriate container, and labeled for treatment of an indicatedcondition, as is further detailed herein.

Miscellaneous Definitions:

Herein, the term “polypeptide” refers to a polymer comprising at least 4amino acid residues linked by peptide bonds or analogs thereof (asdescribed herein), and optionally only by peptide bonds per se. In someembodiments, the polypeptide comprises at least 10 amino acid residuesor analogs thereof. In some embodiments, the polypeptide comprises atleast 20 amino acid residues or analogs thereof. In some embodiments,the polypeptide comprises at least 30 amino acid residues or analogsthereof. In some embodiments, the polypeptide comprises at least 50amino acid residues or analogs thereof. The term “polypeptide”encompasses native polypeptides (e.g., degradation products,synthetically synthesized polypeptides and/or recombinant polypeptides),including, without limitation, native proteins, fragments of nativeproteins and homologs of native proteins and/or fragments thereof; aswell as peptidomimetics (typically, synthetically synthesizedpolypeptides) and peptoids and semipeptoids which are polypeptideanalogs, which may have, for example, modifications rendering thepolypeptides more stable while in a body or more capable of penetratinginto cells. Such modifications include, but are not limited to Nterminus modification, C terminus modification, peptide bondmodification, backbone modifications, and residue modification. Methodsfor preparing peptidomimetic compounds are well known in the art and arespecified, for example, in Quantitative Drug Design, C. A. Ramsden Gd.,Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated byreference as if fully set forth herein. Further details in this respectare provided herein.

Peptide bonds (—CO—NH—) within the polypeptide may be substituted, forexample, by N-methylated amide bonds (—N(CH₃)—CO—), ester bonds(—C(═O)—O—), ketomethylene bonds (—CO—CH₂—), sulfinylmethylene bonds(—S(═O)—CH₂—), α-aza bonds (—NH—N(R)—CO—), wherein R is any alkyl (e.g.,methyl), amine bonds (—CH₂—NH—), sulfide bonds (—CH₂—S—), ethylene bonds(—CH₂—CH₂—), hydroxyethylene bonds (—CH(OH)—CH₂—), thioamide bonds(—CS—NH—), olefinic double bonds (—CH═CH—), fluorinated olefinic doublebonds (—CF═CH—), retro amide bonds (—NH—CO—), peptide derivatives(—N(R)—CH2-CO—), wherein R is the “normal” side chain, naturally presenton the carbon atom.

These modifications can occur at any of the bonds along the polypeptidechain and even at several (2-3) bonds at the same time.

Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted bynon-natural aromatic amino acids such as1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), naphthylalanine,ring-methylated derivatives of Phe, halogenated derivatives of Phe orO-methyl-Tyr.

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) may also include one or more modified amino acids or one or morenon-amino acid monomers (e.g. fatty acids, complex carbohydrates etc).

The term “amino acid” or “amino acids” is understood to include the 20naturally occurring amino acids; those amino acids often modifiedpost-translationally in vivo, including, for example, hydroxyproline,phosphoserine and phosphothreonine; and other unusual amino acidsincluding, but not limited to, 2-aminoadipic acid, hydroxylysine,isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, theterm “amino acid” includes both D- and L-amino acids.

Tables 1 and 2 below list naturally occurring amino acids (Table 1), andnon-conventional or modified amino acids (e.g., synthetic, Table 2)which can be used with some embodiments of the invention.

TABLE 1 Three-Letter One-letter Amino Acid Abbreviation Symbol AlanineAla A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys CGlutamine Gln Q Glutamic Acid Glu E Glycine Gly G Histidine His HIsoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met MPhenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr TTryptophan Trp W Tyrosine Tyr Y Valine Val V Any amino acid as above XaaX

TABLE 2 Non-conventional amino Non-conventional amino acid Code acidCode ornithine Orn hydroxyproline Hyp α-aminobutyric acid Abuaminonorbornyl-carboxylate Norb D-alanine Dalaaminocyclopropane-carboxylate Cpro D-arginine DargN-(3-guanidinopropyl)glycine Narg D-asparagine DasnN-(carbamylmethyl)glycine Nasn D-aspartic acid DaspN-(carboxymethyl)glycine Nasp D-cysteine Dcys N-(thiomethyl)glycine NcysD-glutamine Dgln N-(2-carbamylethyl)glycine Ngln D-glutamic acid DgluN-(2-carboxyethyl)glycine Nglu D-histidine DhisN-(imidazolylethyl)glycine Nhis D-isoleucine DileN-(1-methylpropyl)glycine Nile D-leucine Dleu N-(2-methylpropyl)glycineNleu D-lysine Dlys N-(4-aminobutyl)glycine Nlys D-methionine DmetN-(2-methylthioethyl)glycine Nmet D-omithine DornN-(3-aminopropyl)glycine Norn D-phenylalanine Dphe N-benzylglycine NpheD-proline Dpro N-(hydroxymethyl)glycine Nser D-serine DserN-(1-hydroxyethyl)glycine Nthr D-threonine Dthr N-(3-indolylethyl)glycine Nhtrp D-tryptophan Dtrp N-(p-hydroxyphenyl)glycine NtyrD-tyrosine Dtyr N-(1-methylethyl)glycine Nval D-valine DvalN-methylglycine Nmgly D-N-methylalanine Dnmala L-N-methylalanine NmalaD-N-methylarginine Dnmarg L-N-methylarginine Nmarg D-N-methylasparagineDnmasn L-N-methylasparagine Nmasn D-N-methylasparatate DnmaspL-N-methylaspartic acid Nmasp D-N-methylcysteine DnmcysL-N-methylcysteine Nmcys D-N-methylglutamine Dnmgln L-N-methylglutamineNmgln D-N-methylglutamate Dnmglu L-N-methylglutamic acid NmgluD-N-methylhistidine Dnmhis L-N-methylhistidine NmhisD-N-methylisoleucine Dnmile L-N-methylisolleucine NmileD-N-methylleucine Dnmleu L-N-methylleucine Nmleu D-N-methyllysine DnmlysL-N-methyllysine Nmlys D-N-methylmethionine Dnmmet L-N-methylmethionineNmmet D-N-methylornithine Dnmorn L-N-methylornithine NmornD-N-methylphenylalanine Dnmphe L-N-methylphenylalanine NmpheD-N-methylproline Dnmpro L-N-methylproline Nmpro D-N-methylserine DnmserL-N-methylserine Nmser D-N-methylthreonine Dnmthr L-N-methylthreonineNmthr D-N-methyltryptophan Dnmtrp L-N-methyltryptophan NmtrpD-N-methyltyrosine Dnmtyr L-N-methyltyrosine Nmtyr D-N-methylvalineDnmval L-N-methylvaline Nmval L-norleucine Nle L-N-methylnorleucineNmnle L-norvaline Nva L-N-methylnorvaline Nmnva L-ethylglycine EtgL-N-methyl-ethylglycine Nmetg L-t-butylglycine TbugL-N-methyl-t-butylglycine Nmtbug L-homophenylalanine HpheL-N-methyl-homophenylalanine Nmhphe α-naphthylalanine AnapN-methyl-α-naphthylalanine Nmanap penicillamine PenN-methylpenicillamine Nmpen γ-aminobutyric acid GabuN-methyl-γ-aminobutyrate Nmgabu cyclohexylalanine ChexaN-methyl-cyclohexylalanine Nmchexa cyclopentylalanine CpenN-methyl-cyclopentylalanine Nmcpen α-amino-α-methylbutyrate AabuN-methyl-α-amino-α-methylbutyrate Nmaabu α-aminoisobutyric acid AibN-methyl-α-aminoisobutyrate Nmaib D-α-methylarginine DmargL-α-methylarginine Marg D-α-methylasparagine Dmasn L-α-methylasparagineMasn D-α-methylaspartate Dmasp L-α-methylaspartate MaspD-α-methylcysteine Dmcys L-α-methylcysteine Mcys D-α-methylglutamineDmgln L-α-methylglutamine Mgln D-α-methyl glutamic acid DmgluL-α-methylglutamate Mglu D-α-methylhistidine Dmhis L-α-methylhistidineMhis D-α-methylisoleucine Dmile L-α-methylisoleucine MileD-α-methylleucine Dmleu L-α-methylleucine Mleu D-α-methyllysine DmlysL-α-methyllysine Mlys D-α-methylmethionine Dmmet L-α-methylmethionineMmet D-α-methylornithine Dmorn L-α-methylornithine MornD-α-methylphenylalanine Dmphe L-α-methylphenylalanine MpheD-α-methylproline Dmpro L-α-methylproline Mpro D-α-methylserine DmserL-α-methylserine Mser D-α-methylthreonine Dmthr L-α-methylthreonine MthrD-α-methyltryptophan Dmtrp L-α-methyltryptophan Mtrp D-α-methyltyrosineDmtyr L-α-methyltyrosine Mtyr D-α-methylvaline Dmval L-α-methylvalineMval N-cyclobutylglycine Ncbut L-α-methylnorvaline MnvaN-cycloheptylglycine Nchep L-α-methylethylglycine MetgN-cyclohexylglycine Nchex L-α-methyl-t-butylglycine MtbugN-cyclodecylglycine Ncdec L-α-methyl-homophenylalanine MhpheN-cyclododecylglycine Ncdod α-methyl-α-naphthylalanine ManapN-cyclooctylglycine Ncoct α-methylpenicillamine MpenN-cyclopropylglycine Ncpro α-methyl-γ-aminobutyrate MgabuN-cycloundecylglycine Ncund α-methyl-cyclohexylalanine MchexaN-(2-aminoethyl)glycine Naeg α-methyl-cyclopentylalanine McpenN-(2,2-diphenylethyl)glycine NbhmN-(N-(2,2-diphenylethyl)carbamylmethyl-glycine NnbhmN-(3,3-diphenylpropyl)glycine NbheN-(N-(3,3-diphenylpropyl)carbamylmethyl-glycine Nnbhe1-carboxy-1-(2,2-diphenylethylamino)cyclopropane Nmbc1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Tic phosphoserine pSerphosphothreonine pThr phosphotyrosine pTyr O-methyl-tyrosine2-aminoadipic acid hydroxylysine

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) are preferably utilized in a linear form, although it will beappreciated that in cases where cyclicization does not severelyinterfere with polypeptide characteristics, cyclic forms of thepolypeptide can also be utilized.

In some embodiments of any one of the embodiments described herein, thepolypeptide is water-soluble.

Herein, the term “water-soluble” refers to a compound having asolubility of at least 1 gram per liter in an aqueous solution at pH 7.

Water-soluble polypeptides preferably include one or more non-natural ornatural polar amino acids, including but not limited to serine andthreonine which are capable of increasing polypeptide water-solubilitydue to their hydroxyl-containing side chain. Optionally, a homolog of apolypeptide is selected so as to be more water-soluble than the parentpolypeptide, for example, by replacing one or more amino acids in thepolypeptide with polar amino acids.

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) may be synthesized by any techniques that are known to thoseskilled in the art of peptide synthesis. For solid phase peptidesynthesis, a summary of the many techniques may be found in J. M.Stewart and J. D. Young, Solid Phase Peptide Synthesis, W. H. FreemanCo. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins andPeptides, vol. 2, p. 46, Academic Press (New York), 1973. For classicalsolution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1,Academic Press (New York), 1965.

In general, these methods comprise the sequential addition of one ormore amino acids or suitably protected amino acids to a growingpolypeptide chain. Normally, either the amino or carboxyl group of thefirst amino acid is protected by a suitable protecting group. Theprotected or derivatized amino acid can then either be attached to aninert solid support or utilized in solution by adding the next aminoacid in the sequence having the complimentary (amino or carboxyl) groupsuitably protected, under conditions suitable for forming the amidelinkage. The protecting group is then removed from this newly addedamino acid residue and the next amino acid (suitably protected) is thenadded, and so forth. After all the desired amino acids have been linkedin the proper sequence, any remaining protecting groups (and any solidsupport) are removed sequentially or concurrently, to afford the finalpolypeptide compound. By simple modification of this general procedure,it is possible to add more than one amino acid at a time to a growingchain, for example, by coupling (under conditions which do not racemizechiral centers) a protected tripeptide with a properly protecteddipeptide to form, after deprotection, a pentapeptide and so forth.Further description of peptide synthesis is disclosed in U.S. Pat. No.6,472,505.

A preferred method of preparing the polypeptide compounds of someembodiments of the invention (e.g., a therapeutically active agentand/or a protease inhibitor described herein) involves solid phasepeptide synthesis.

Large scale polypeptide synthesis is described by Andersson et al.[Biopolymers 2000; 55:227-250].

Herein, a “homolog” of a given polypeptide refers to a polypeptide thatexhibits at least 80% homology, preferably at least 90% homology, andmore preferably at least 95% homology, and more preferably at least 98%homology to the given polypeptide. In some embodiments, a homolog of agiven polypeptide further shares a therapeutic activity with the givenpolypeptide. The percentage of homology refers to the percentage ofamino acid residues in a first polypeptide sequence which match acorresponding residue of a second polypeptide sequence to which thefirst polypeptide is being compared. Generally, the polypeptides arealigned to give maximum homology. A variety of strategies are known inthe art for performing comparisons of amino acid or nucleotide sequencesin order to assess degrees of identity, including, for example, manualalignment, computer assisted sequence alignment and combinationsthereof. A number of algorithms (which are generally computerimplemented) for performing sequence alignment are widely available, orcan be produced by one of skill in the art. Representative algorithmsinclude, e.g., the local homology algorithm of Smith and Waterman (Adv.Appl. Math., 1981, 2: 482); the homology alignment algorithm ofNeedleman and Wunsch (J. Mol. Biol., 1970, 48: 443); the search forsimilarity method of Pearson and Lipman (Proc. Natl. Acad. Sci. (USA),1988, 85: 2444); and/or by computerized implementations of thesealgorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the WisconsinGenetics Software Package Release 7.0, Genetics Computer Group, 575Science Dr., Madison, Wis.). Readily available computer programsincorporating such algorithms include, for example, BLASTN, BLASTP,Gapped BLAST, PILEUP, CLUSTALW etc. When utilizing BLAST and GappedBLAST programs, default parameters of the respective programs may beused. Alternatively, the practitioner may use non-default parametersdepending on his or her experimental and/or other requirements (see forexample, the Web site having URL www(dot)ncbi(dot)nlm(dot)nih(dot)gov).

It is expected that during the life of a patent maturing from thisapplication many relevant therapeutically active agents and manyrelevant treatments of conditions by therapeutically active agents willbe developed, and the scope of the phrases “therapeutically activeagent” and “condition treatable by . . . therapeutically active agent”are intended to include all such new technologies a priori.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

The word “exemplary” is used herein to mean “serving as an example,instance or illustration”. Any embodiment described as “exemplary” isnot necessarily to be construed as preferred or advantageous over otherembodiments and/or to exclude the incorporation of features from otherembodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features unless such features conflict.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a therapeutically active agent” may include a plurality ofcompounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

In some embodiments of any one of the embodiments described herein, theunit dosage form and/or composition according to any of the aspectsdescribed herein is for use in the treatment of a condition treatable byoral administration of the therapeutically active agent (e.g., acondition described herein).

According to another aspect of embodiments of the invention, there isprovided a use of a unit dosage form and/or composition according to anyof the aspects described herein in the preparation of a medicament foruse in the treatment of a condition treatable by oral administration ofthe therapeutically active agent (e.g., a condition described herein).

According to another aspect of embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof (e.g., a condition and therapeutically active agent describedherein), the method comprising orally administering to the subject aunit dosage form and/or composition according to any of the aspectsdescribed herein which comprises the therapeutically active agent.

Examples of conditions treatable according to embodiments of theinvention include, without limitation, hyperglycemia, for example, indiabetes (e.g., wherein the therapeutically active agent is an insulinor a GLP-1, or another agent which reduces blood glucose levels);hypoglycemia (e.g., wherein the therapeutically active agent is aglucagon, or another agent which increases blood glucose levels);osteoporosis (e.g., wherein the therapeutically active agent is a PTH orfragment thereof); and hypoparathyroidism (e.g., wherein thetherapeutically active agent is a PTH or fragment thereof).

The skilled person will be capable of determining which conditions aretreatable by oral administration of any given therapeutically activeagent.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in anon-limiting fashion.

Materials:

8-Aminocaprylic acid was obtained from Alfa-Aesar.

O-acetylsalicyloyl chloride was obtained from Sigma-Aldrich.

Soybean trypsin inhibitor was obtained from Sigma-Aldrich.

Teriparatide was obtained from Bachem.

Sodium bicarbonate was obtained from Merck.

SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) was prepared byreacting O-acetylsalicyloyl chloride with 8-aminocaprylic acid.

Example 1 Effect of Antacid on Release of SNAG

Two tablet formulations were prepared, having the same amounts of SNAC,trypsin inhibitor and teriparatide (parathyroid hormone (1-34)), whereinone formulation further contained 100 mg sodium bicarbonate and theother formulation did not contain sodium bicarbonate. The tablets werein a form of a homogeneous mixture.

Each tablet formulation was subjected to a dissolution test in 100 ml ofsimulated gastric buffer (without pepsin), pH 2.0, at 37° C., accordingto USP 23 Apparatus 2 (paddle) with 50 rotations per minute. The amountof released SNAC in each sample was determined chromatographically,using an HPLC apparatus with Cosmosil™ 5 C18-MS-II (4.6 ID×250 mm)column. Mobile phase consisted of 50% acetonitrile and 50% phosphoricacid solution (0.1%). Flow rate was 1 ml/minute and injection volume was25 μl. Amount of released SNAC was calculated as a percentage of theamount of SNAC in the formulation.

As shown in FIG. 8, sodium bicarbonate considerably enhanced thedissolution of SNAC in tablets, and preserved the soluble fraction ofSNAC.

These results indicate that formulation with an antacid such as sodiumbicarbonate can considerably enhance the effect of the absorptionenhancer SNAC.

Example 2

Effect of Antacid on Pharmacokinetic Profile of Orally AdministeredParathyroid Hormone (PTH)

An open label comparative pharmacokinetic study was performed on tenhealthy volunteers. On different visits, each volunteer received thesame oral tablet containing 0.75 mg of teriparatide, a recombinant formof parathyroid hormone (1-34) (PTH(1-34)). In the first visit, thetablet was administered with 150 ml water, whereas in the second visitthe tablet was administered with 150 ml of 3 mg/ml sodium bicarbonateaqueous solution.

The formulation was composed of teriparatide (0.75 mg), SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate), soybean trypsin inhibitor (SBTI)and a small amount of magnesium stearate.

Tablets were administered in the morning after an 8-hour overnight fast.At each visit a standard meal was provided 3 hours after drugadministration. Patients did not eat nor drink alcoholic or caffeinatedbeverages. There was a two week period between the two visits.

To determine PTH(1-34) concentrations, blood samples (4 ml each) weredrawn via an indwelling catheter from the forearm vein at predeterminedtime points during each visit. The cannula was flushed with 1.5 mlnormal saline after each sampling. In addition, to avoid sampledilution, 1 ml of blood was drawn and discarded before the next sample.The blood samples were taken at the following times points: baseline(predose), 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes,60 minutes, 75 minutes, 90 minutes, 105 minutes, 2 hours, 3 hours, 4hours and 5 hours post-administration. Each blood sample was collectedinto a single tube containing EDTA (ethylenediaminetetraacetic acid) andplaced on ice. Within 15 minutes of blood collection, samples werecentrifuged for 10 minutes at 4° C. (2500 rotations per minute) and theplasma was separated and divided into two or three aliquots. Eachaliquot was transferred into appropriately labeled polypropylene tubesand stored at approximately −20° C. pending analysis. PTH(1-34) levelswere measured using an IDS-iSYS automated assay for the measurement ofintact PTH(1-34) in human plasma or serum. The results of the assay donot include levels of PTH(1-84) such as endogenous PTH. Relativeabsorption was determined based on the AUC (area under curve) parameter.

As shown in FIG. 9, co-administration with sodium bicarbonate solutionincreased absorption of PTH(1-34) from an orally administeredformulation by about 35%, in comparison with co-administration of theformulation with water.

These results indicate that co-administration with an antacid enhancesthe ability of SNAC to promote absorption of therapeutically activeagents.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A pharmaceutical composition for oral administration of a therapeutic active agent, the composition comprising a therapeutically active agent, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), and at least one antacid compound in a total amount of at least 0.001 molar equivalent of base.
 2. The composition of claim 1, further comprising at least one trypsin inhibitor.
 3. The composition of claim 2, wherein said at least one trypsin inhibitor comprises soybean trypsin inhibitor.
 4. The composition of claim 1, wherein said at least one antacid compound is selected from the group consisting of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminum hydroxide.
 5. The composition of claim 1, wherein said therapeutically active agent is selected from the group consisting of parathyroid hormone and a fragment thereof.
 6. The composition of claim 1, wherein said therapeutically active agent comprises teriparatide.
 7. The composition of claim 1, being formulated such that absorption of said therapeutically active agent following oral administration of the composition is characterized by a bioavailability of said therapeutically active agent which is at least 10% higher than a bioavailability of said therapeutically active agent following oral administration of a composition comprising said therapeutically active agent and said SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) without said at least one antacid compound.
 8. The composition of claim 1, being in a form of a homogeneous mixture.
 9. The composition of claim 1, being formulated as a solid unit dosage form.
 10. The composition of claim 9, being formulated as a tablet.
 11. The composition of claim 9, wherein said unit dosage form is soluble in gastric fluid.
 12. A method of treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof, the method comprising orally administering to the subject the composition of claim
 1. 13. A method of treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof, the method comprising co-administering to the subject, by oral administration, an antacid composition comprising at least one antacid compound and/or at least one gastric acid secretion inhibitor, and a composition comprising said therapeutically active agent and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), wherein said at least one antacid compound is selected from the group consisting of calcium citrate, calcium gluconate, sodium gluconate, sodium citrate, sodium hydroxide, potassium gluconate, potassium citrate, potassium hydroxide, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum gluconate, aluminum citrate, and aluminum hydroxide, and said at least one antacid compound is administered in a total amount of at least 1 mg.
 14. A pharmaceutical composition unit dosage form for oral administration of a therapeutically active agent, the unit dosage form comprising: a core comprising the therapeutically active agent and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate); and an external layer comprising at least one protective agent selected from the group consisting of an antacid compound in a total amount of at least 0.001 molar equivalent of base and a protease inhibitor.
 15. The unit dosage form of claim 14, wherein said external layer is devoid of said therapeutically active agent.
 16. The unit dosage form of claim 14, wherein said at least one protease inhibitor comprises at least one trypsin inhibitor.
 17. The unit dosage form of claim 14, wherein said at least one antacid compound is selected from the group consisting of calcium carbonate, calcium citrate, calcium gluconate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminum hydroxide.
 18. The unit dosage form of claim 14, wherein said therapeutically active agent is selected from the group consisting of parathyroid hormone and a fragment thereof.
 19. The unit dosage form of claim 14, being formulated such that absorption of said therapeutically active agent following oral administration of the unit dosage form is characterized by a bioavailability of said therapeutically active agent which is at least 10% higher than a bioavailability of said therapeutically active agent following oral administration of said core without said external layer.
 20. A method of treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof, the method comprising orally administering to the subject the unit dosage form of claim
 14. 